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Wang, Juanjuan, Ningning Zhu, Xiaomin Su, Yunhuan Gao, and Rongcun Yang. "Gut-Microbiota-Derived Metabolites Maintain Gut and Systemic Immune Homeostasis." Cells 12, no. 5 (March 2, 2023): 793. http://dx.doi.org/10.3390/cells12050793.
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The gut microbiota, including bacteria, archaea, fungi, viruses and phages, inhabits the gastrointestinal tract. This commensal microbiota can contribute to the regulation of host immune response and homeostasis. Alterations of the gut microbiota have been found in many immune-related diseases. The metabolites generated by specific microorganisms in the gut microbiota, such as short-chain fatty acids (SCFAs), tryptophan (Trp) and bile acid (BA) metabolites, not only affect genetic and epigenetic regulation but also impact metabolism in the immune cells, including immunosuppressive and inflammatory cells. The immunosuppressive cells (such as tolerogenic macrophages (tMacs), tolerogenic dendritic cells (tDCs), myeloid-derived suppressive cells (MDSCs), regulatory T cells (Tregs), regulatory B cells (Breg) and innate lymphocytes (ILCs)) and inflammatory cells (such as inflammatory Macs (iMacs), DCs, CD4 T helper (Th)1, CD4Th2, Th17, natural killer (NK) T cells, NK cells and neutrophils) can express different receptors for SCFAs, Trp and BA metabolites from different microorganisms. Activation of these receptors not only promotes the differentiation and function of immunosuppressive cells but also inhibits inflammatory cells, causing the reprogramming of the local and systemic immune system to maintain the homeostasis of the individuals. We here will summarize the recent advances in understanding the metabolism of SCFAs, Trp and BA in the gut microbiota and the effects of SCFAs, Trp and BA metabolites on gut and systemic immune homeostasis, especially on the differentiation and functions of the immune cells.
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Su, Xiaomin, Yunhuan Gao, and Rongcun Yang. "Gut Microbiota-Derived Tryptophan Metabolites Maintain Gut and Systemic Homeostasis." Cells 11, no. 15 (July 25, 2022): 2296. http://dx.doi.org/10.3390/cells11152296.
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Tryptophan is an essential amino acid from dietary proteins. It can be metabolized into different metabolites in both the gut microbiota and tissue cells. Tryptophan metabolites such as indole-3-lactate (ILA), indole-3-acrylate (IAC), indole-3-propionate (IPA), indole-3-aldehyde (IAID), indoleacetic acid (IAA), indole-3-acetaldehyde and Kyn can be produced by intestinal microorganisms through direct Trp transformation and also, partly, the kynurenine (Kyn) pathway. These metabolites play a critical role in maintaining the homeostasis of the gut and systematic immunity and also potentially affect the occurrence and development of diseases such as inflammatory bowel diseases, tumors, obesity and metabolic syndrome, diseases in the nervous system, infectious diseases, vascular inflammation and cardiovascular diseases and hepatic fibrosis. They can not only promote the differentiation and function of anti-inflammatory macrophages, Treg cells, CD4+CD8αα+ regulatory cells, IL-10+ and/or IL-35+B regulatory cells but also IL-22-producing innate lymphoid cells 3 (ILC3), which are involved in maintaining the gut mucosal homeostasis. These findings have important consequences in the immunotherapy against tumor and other immune-associated diseases. We will summarize here the recent advances in understanding the generation and regulation of tryptophan metabolites in the gut microbiota, the role of gut microbiota-derived tryptophan metabolites in different immune cells, the occurrence and development of diseases and immunotherapy against immune-associated diseases.
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Daien, C., J. Tan, R. Audo, J. Mielle, and L. Macia. "OP0131 GUT DERIVED ACETATE PROMOTES REGULATORY B CELLS WITH ANTI-INFLAMMATORY EFFECTS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 85.2–85. http://dx.doi.org/10.1136/annrheumdis-2020-eular.4924.
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Background:Regulatory B cells (Bregs) are defective in many auto-immune diseases, i.e. rheumatoid arthritis (RA). The short-chain fatty acid (SCFA) acetate, derived mostly from gut microbial fermentation of dietary fiber, promotes anti-inflammatory regulatory T cells and protects mice from type 1 diabetes and colitis. We hypothesized that acetate could be a good candidate to promote Bregs in auto-immune diseases.Objectives:To assess the effect of acetate on Breg number and function,in vitroandin vivoin mice and humans.Methods:Bregs were defined as IL-10 producing regulatory B cells (B10 cells). Their number was assessed after overnight exposure to acetate (Ac 10 mM) and 4 hours of CpG, ionomycin and PMA in mice and after 24 hours of acetate +/- CpG and 4 hours of ionomycin and PMA in humans. Acetate was given to mice either intraperitoneally (twice at a 12-hour interval) or in drinking water for 3 weeks. Acetate-treated B cells were transferred to mice with collagen-antibody -induced arthritis to assess their function. To decipher the mechanisms behind the effect of acetate, we used inhibitors of GPR43 (CATPB), ATP synthase (oligomycin), glycolysis (2-DG), ACSS2 and ACLY and assessed protein lysine acetylation by flow cytometry on human B cells. Acetate and B10 cells were also assessed before and after a 7-day high-fibre diet in 12 healthy volunteers.Results:In mice, acetate promoted B10 cell differentiation bothin vitro(medians [IQR] 3.1 [0.4-3.7] and 9.9 [5.9-17.6]% of B for CpG and CpG+Ac respectively, p=0.002) andin vivowhen intraperitoneal injected(22 [14-29] and 31 [25-37]% of B for PBS and acetate respectively,p=0.03) or added to drinking water (17 [6-25] and 39 [26-40]% of B for water or acetate respectively, p=0.02). Adoptive transfer of acetate-treated B cells protected mice from arthritis compared to non-exposed B cells (ANOVA p=0.008). Acetate also promoted B10 cells from human blood cells (2.5 [1.6-2.7] and 3.4 [2.6-4.5] for unstimulated [Un] and Ac respectively, p=0.0001). Conversely to CpG, acetate specifically promoted IL-10, with no impact or a decrease of proinflammatory cytokines (IL-6: 17 [5-29]; 12 [3-21] and 40 [20-47]% B cells for Un, Ac and CpG respectively, p<0.01 for all comparisons and TNF-a: 48 [29-61]; 41 [28-67] and 69 [64-78]% B cells for Un, Ac and CpG respectively, p<0.01 for CpG vs Un or Ac, NS for acetate vs Un). Inhibition of GPR43 and ACLY did not impact acetate response, while inhibition of glycolysis significantly decreased its effect. Blockade of ACSS2, converting acetate into acetyl-CoA, decreased acetate-induced B10 cells. Acetate was associated with an increase of protein lysine acetylation which was not observed in presence of CpG alone, suggesting a different mechanism of action (2.0 [1.3-3.4]; 3.3 [2.4-5.4] and 1.4 [0.5-1.7]% B cells for Un, Ac and CpG respectively, p=0.002 for Un vs Ac, NS with CpG). Conversion of acetate into acetyl-CoA could thus be used for the acetylation of cytoplasmic protein, a post-translational modification that regulates key cellular processes, including energy metabolism. In addition, B10 cells had significantly more lysine-acetylated proteins than IL-10negB cells or TNF+B cells (5.3[3.9-7.3]; 3.2 [2.4-5.4] and 3.9 [2.7-6.2] % of B for B10, IL-10negB cells or TNF+B cells respectively, p<0.01 for all comparisons). Finally, dietary fiber supplementation in healthy individuals was associated with increased acetate and B10 cells in the blood, which were significantly correlated (R2=0.20, p=0.02).Conclusion:Our results suggest that acetate induces functional Bregs, through its conversion into acetyl-CoA, used for cell metabolism and protein acetylation. Delivery of acetate or acetate producing diets or bacteria might be a promising approach to restore Bregs in non-communicable diseases such as RA in which they are defective.Disclosure of Interests:Claire DAIEN Grant/research support from: from Pfizer, Abbvie, Roche-Chugaï, Novartis, Abivax, Sandoz, Consultant of: Abbvie, Abivax, BMS, MSD, Roche-Chugaï, Lilly, Novartis, Speakers bureau: Abbvie, Abivax, BMS, MSD, Roche-Chugaï, Lilly, Novartis, Jian Tan: None declared, Rachel Audo: None declared, Julie Mielle: None declared, Laurence Macia: None declared
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Zheng, Mingzhu, Kairui Mao, Difeng Fang, Dan Li, Jun Lyu, Dingkang Peng, Xi Chen, et al. "B cell residency but not T cell–independent IgA switching in the gut requires innate lymphoid cells." Proceedings of the National Academy of Sciences 118, no. 27 (June 29, 2021): e2106754118. http://dx.doi.org/10.1073/pnas.2106754118.
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Immunoglobulin A (IgA)–producing plasma cells derived from conventional B cells in the gut play an important role in maintaining the homeostasis of gut flora. Both T cell–dependent and T cell–independent IgA class switching occurs in the lymphoid structures in the gut, whose formation depends on lymphoid tissue inducers (LTis), a subset of innate lymphoid cells (ILCs). However, our knowledge on the functions of non-LTi helper-like ILCs, the innate counter parts of CD4 T helper cells, in promoting IgA production is still limited. By cell adoptive transfer and utilizing a unique mouse strain, we demonstrated that the generation of IgA-producing plasma cells from B cells in the gut occurred efficiently in the absence of both T cells and helper-like ILCs and without engaging TGF-β signaling. Nevertheless, B cell recruitment and/or retention in the gut required functional NKp46−CCR6+ LTis. Therefore, while CCR6+ LTis contribute to the accumulation of B cells in the gut through inducing lymphoid structure formation, helper-like ILCs are not essential for the T cell–independent generation of IgA-producing plasma cells.
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Tsuda, Masato, Hiraku Okada, Natsuki Kojima, Fumiya Ishihama, Yuhei Muraki, Toshiki Oguma, Nanako Hattori, et al. "Cecal Patches Generate Abundant IgG2b-Bearing B Cells That Are Reactive to Commensal Microbiota." Journal of Immunology Research 2022 (May 4, 2022): 1–13. http://dx.doi.org/10.1155/2022/3974141.
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Gut-associated lymphoid tissue (GALT), such as Peyer’s patches (PPs), are key inductive sites that generate IgA+ B cells, mainly through germinal center (GC) responses. The generation of IgA+ B cells is promoted by the presence of gut microbiota and dietary antigens. However, the function of GALT in the large intestine, such as cecal patches (CePs) and colonic patches (CoPs), and their regulatory mechanisms remain largely unknown. In this study, we demonstrate that the CePs possess more IgG2b+ B cells and have fewer IgA+ B cells than those in PPs from BALB/c mice with normal gut microbiota. Gene expression analysis of postswitched transcripts supported the differential expression of dominant antibody isotypes in B cells in GALT. Germ-free (GF) mice showed diminished GC B cells and had few IgA+ or IgG2b+ switched B cells in both the small and large intestinal GALT. In contrast, myeloid differentiation factor 88- (MyD88-) deficient mice exhibited decreased GC B cells and presented with reduced numbers of IgG2b+ B cells in CePs but not in PPs. Using ex vivo cell culture, we showed that CePs have a greater capacity to produce total and microbiota-reactive IgG2b, in addition to microbiota-reactive IgA, than the PPs. In line with the frequency of GC B cells and IgG2b+ B cells in CePs, there was a decrease in the levels of microbiota-reactive IgG2b and IgA in the serum of GF and MyD88-deficient mice. These data suggest that CePs have a different antibody production profile compared to PPs. Furthermore, the innate immune signals derived from gut microbiota are crucial for generating the IgG2b antibodies in CePs.
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Osman, Mohammad, Janice Russell, and D. Neil Granger. "Lymphocyte-derived interferon-γ mediates ischemia-reperfusion-induced leukocyte and platelet adhesion in intestinal microcirculation." American Journal of Physiology-Gastrointestinal and Liver Physiology 296, no. 3 (March 2009): G659—G663. http://dx.doi.org/10.1152/ajpgi.90495.2008.
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Although previous studies have implicated lymphocytes in the gut microvascular and inflammatory responses to ischemia-reperfusion (I/R), the lymphocyte population and lymphocyte-derived products that mediate these responses have not been defined. Platelet and leukocyte adhesion was measured in intestinal postcapillary venules of wild-type (WT) mice and mice genetically deficient in either CD4+ T cells (CD4−/−), CD8+ T cells (CD8−/−), B cells (B cell−/−), or interferon-γ (IFN-γ−/−) subjected to 45 min of ischemia and 4 h of reperfusion. The I/R-induced platelet and leukocyte recruitment responses were also evaluated following adoptive transfer of WT splenocytes into CD4−/−, CD8−/−, B cell−/−, and IFN-γ−/− mice. WT mice exposed to gut I/R exhibited significant increases in the adhesion of both platelets and leukocytes, compared with sham-WT mice. These blood cell adhesion responses to I/R were greatly attenuated in CD4−/−, CD8−/−, B cell−/−, and IFN-γ−/− mice. Adoptive transfer of WT splenocytes restored the WT responses to I/R in all mutants except the B cell−/− mice. These findings implicate both T and B cells and lymphocyte-derived IFN-γ as mediators of the proinflammatory and prothrombogenic phenotype assumed by intestinal microvessels after I/R.
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Yaguchi, Junko, and Shunsuke Yaguchi. "Evolution of nitric oxide regulation of gut function." Proceedings of the National Academy of Sciences 116, no. 12 (March 4, 2019): 5607–12. http://dx.doi.org/10.1073/pnas.1816973116.
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Although morphologies are diverse, the common pattern in bilaterians is for passage of food in the gut to be controlled by nerves and endodermally derived neuron-like cells. In vertebrates, nitric oxide (NO) derived from enteric nerves controls relaxation of the pyloric sphincter. Here, we show that in the larvae of sea urchins, there are endoderm-derived neuronal nitric oxide synthase (nNOS)-positive cells expressing pan-neural marker, Synaptotagmin-B (SynB), in sphincters and that NO regulates the relaxation of the pyloric sphincter. Our results indicate that NO-dependent pylorus regulation is a shared feature within the deuterostomes, and we speculate that it was a characteristic of stem deuterostomes.
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Sahputra, Rinal, Emma A. Murphy, Ruth Forman, Iris Mair, Muhammad Z. H. Fadlullah, Ari Waisman, Werner Muller, and Kathryn J. Else. "Investigating the importance of B cells and antibodies during Trichuris muris infection using the IgMi mouse." Journal of Molecular Medicine 98, no. 9 (August 10, 2020): 1301–17. http://dx.doi.org/10.1007/s00109-020-01954-3.
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Abstract The IgMi mouse has normal B cell development; its B cells express an IgM B cell receptor but cannot class switch or secrete antibody. Thus, the IgMi mouse offers a model system by which to dissect out antibody-dependent and antibody-independent B cell function. Here, we provide the first detailed characterisation of the IgMi mouse post-Trichuris muris (T. muris) infection, describing expulsion phenotype, cytokine production, gut pathology and changes in T regulatory cells, T follicular helper cells and germinal centre B cells, in addition to RNA sequencing (RNA seq) analyses of wild-type littermates (WT) and mutant B cells prior to and post infection. IgMi mice were susceptible to a high-dose infection, with reduced Th2 cytokines and elevated B cell-derived IL-10 in mesenteric lymph nodes (MLN) compared to controls. A low-dose infection regime revealed IgMi mice to have significantly more apoptotic cells in the gut compared to WT mice, but no change in intestinal inflammation. IL-10 levels were again elevated. Collectively, this study showcases the potential of the IgMi mouse as a tool for understanding B cell biology and suggests that the B cell plays both antibody-dependent and antibody-independent roles post high- and low-dose T. muris infection. Key messages During a high-dose T. muris infection, B cells are important in maintaining the Th1/Th2 balance in the MLN through an antibody-independent mechanism. High levels of IL-10 in the MLN early post-infection, and the presence of IL-10-producing B cells, correlates with susceptibility to T. muris infection. B cells maintain gut homeostasis during chronic T. muris infection via an antibody-dependent mechanism.
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Kim, Chang H. "Control of lymphocyte functions by gut microbiota-derived short-chain fatty acids." Cellular & Molecular Immunology 18, no. 5 (April 13, 2021): 1161–71. http://dx.doi.org/10.1038/s41423-020-00625-0.
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AbstractA mounting body of evidence indicates that dietary fiber (DF) metabolites produced by commensal bacteria play essential roles in balancing the immune system. DF, considered nonessential nutrients in the past, is now considered to be necessary to maintain adequate levels of immunity and suppress inflammatory and allergic responses. Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, are the major DF metabolites and mostly produced by specialized commensal bacteria that are capable of breaking down DF into simpler saccharides and further metabolizing the saccharides into SCFAs. SCFAs act on many cell types to regulate a number of important biological processes, including host metabolism, intestinal functions, and immunity system. This review specifically highlights the regulatory functions of DF and SCFAs in the immune system with a focus on major innate and adaptive lymphocytes. Current information regarding how SCFAs regulate innate lymphoid cells, T helper cells, cytotoxic T cells, and B cells and how these functions impact immunity, inflammation, and allergic responses are discussed.
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Weisel, Nadine M., Florian J. Weisel, Donna L. Farber, Lisa A. Borghesi, Yufeng Shen, Wenji Ma, Eline T. Luning Prak, and Mark J. Shlomchik. "Comprehensive analyses of B-cell compartments across the human body reveal novel subsets and a gut-resident memory phenotype." Blood 136, no. 24 (December 10, 2020): 2774–85. http://dx.doi.org/10.1182/blood.2019002782.
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Abstract Although human B cells have been extensively studied, most reports have used peripheral blood as a source. Here, we used a unique tissue resource derived from healthy organ donors to deeply characterize human B-cell compartments across multiple tissues and donors. These datasets revealed that B cells in the blood are not in homeostasis with compartments in other tissues. We found striking donor-to-donor variability in the frequencies and isotype of CD27+ memory B cells (MBCs). A comprehensive antibody-based screen revealed markers of MBC and allowed identification of novel MBC subsets with distinct functions defined according to surface expression of CD69 and CD45RB. We defined a tissue-resident MBC phenotype that was predominant in the gut but absent in blood. RNA-sequencing of MBC subsets from multiple tissues revealed a tissue-resident MBC gene signature as well as gut- and spleen-specific signatures. Overall, these studies provide novel insights into the nature and function of human B-cell compartments across multiple tissues.
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Cen, Selena, Nathalie Simard, and Christopher Paige. "B cell differentiation governed by distinct microenvironments (LYM7P.622)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 200.14. http://dx.doi.org/10.4049/jimmunol.194.supp.200.14.
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Abstract B cell differentiation is regulated by the surrounding microenvironment, which produces cytokines, chemokines, and adhesion molecules that guide B cell commitment and differentiation. The gastrointestinal tract, in constant interaction with microbiota, constitutes a distinctive microenvironment for B cell differentiation. While the bone marrow and spleen contain few IgA+ cells, the gut lamina propria is largely colonized by IgA+ cells, which contain a subset of myeloid-like plasma cells expressing IgA, TNFα, iNOS, CD11c, Ly6C and Ly6G. Whether the bone marrow stroma produces inhibitory factors for IgA+ cell generation or the gut lamina propria stroma produces inducing factors needs further investigation. We developed an in vitro system to co-culture stromal cells with B cells to characterize the signals necessary to generate IgA+ cells. It was found that intestinal microbial components along with the intestinal lamina propria stromal cells played an important role in the emergence of both IgA+ and myeloid-like plasma cells. Interestingly, bone marrow and spleen-derived stroma showed an inhibitory effect on the generation of IgA+ cells. Stromal soluble factors (e.g. IL-1, IL-6, and MCP-1) might play a role in the guidance of B cell IgA switching, proliferation, survival, and differentiation. These experiments will provide a better understanding of the impact of microenvironments in shaping B cell development, and we will identify the molecular mechanisms they use.
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Lanning, Dennis, and Katherine Knight. "Role of CXCL12 and its receptor, CXCR4, in diversification of the rabbit primary antibody repertoire (133.3)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 133.3. http://dx.doi.org/10.4049/jimmunol.184.supp.133.3.
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Abstract The antibody repertoire of early postnatal rabbits is of limited diversity due to preferential V gene usage during VDJ gene rearrangement. Early in life, rabbit B cells expand this repertoire by diversifying their VDJ genes in gut-associated lymphoid tissue. VDJ gene diversification begins around 1 week of age, in B cells located in the basolateral region of nascent follicles. Because these B cells share similarities with B cells in germinal center dark zones, we hypothesized that activated B cells localize to the basolateral region in response to the chemokine CXCL12. To test this hypothesis, we examined B cell expression of CXCR4, the CXCL12 receptor, by in situ hybridization. We found that B cells in the basolateral region, but not those located elsewhere in the follicle, expressed CXCR4. Because antibody repertoire diversification requires signals derived from intestinal commensals, we further examined CXCR4 expression in appendices that were kept sterile by surgical ligation at birth. We found that B cells in these appendices did not express CXCR4 and did not diversify their VDJ genes. By contrast, we detected CXCL12 expression in both conventional and sterile appendices, demonstrating that it is not dependent on commensal-derived signals. Our results suggest that B cells activated by microbial-derived signals upregulate CXCR4 and migrate to the basolateral region of the follicle, likely in response to CXCL12, where they proliferate and diversify their VDJ genes.
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Aihara, Fumiaki, Michael P. Breen, Feng Feng, Rachel Fearns, Joseph P. Mizgerd, and Thomas B. Kepler. "The Influence of The Lung Virome on Pulmonary B cells." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 198.14. http://dx.doi.org/10.4049/jimmunol.202.supp.198.14.
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Abstract The human microbiome is a complex and diverse environment that is implicated in human health and disease. Major locations that host a microbiome include the gut, respiratory system, and the urogenital tracts. While there have been steady advances of the effect of our commensal flora in regions such as the gut microbiome, the impact of the pulmonary microbiome, specifically the viral arm of the microbiome (virome), remains unclear and under-researched. Recent studies have shown that pulmonary viruses can influence disease susceptibility to the benefit, or detriment, to the host. Despite increasing evidence that the lung virome influences human health through the immune system, the direct effects on the host immune system remain unclear. We hypothesize that the chronic presence of the lung virome influences the pulmonary B cell repertoire. The constant exposure to pulmonary virus can generate a unique B cell repertoire independent of peripheral B cells that is tailored specifically towards pulmonary viruses. To address this hypothesis, we have utilized a single-cell B cell culture system to amplify human lung-derived memory B cells (MBCs) from limited human donor samples. By analyzing these MBCs at the genetic level by RNA sequencing and protein level by antigen affinity from secreted antibodies, we can begin to understand the impact of the lung virome on the pulmonary B cell repertoire.
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Rocha, B., P. Vassalli, and D. Guy-Grand. "Thymic and extrathymic origins of gut intraepithelial lymphocyte populations in mice." Journal of Experimental Medicine 180, no. 2 (August 1, 1994): 681–86. http://dx.doi.org/10.1084/jem.180.2.681.
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We have investigated the origin of intraepithelial lymphocytes (IEL) populations in the murine gut, using reconstitution experiments in which the presence of thymus-derived cells of host or donor origin is rigorously controlled: RAG-/- mutant mice which have no T cells, were injected either with the bone marrow (BM) cells of nude mice or with selected peripheral lymph node (LN) T cells of euthymic mice. In thymectomized RAG-/- mice, injection of BM cells from nude mice led, after 2 mo, to the development of a peripheral B cell compartment and to the appearance, in the gut, of IEL bearing homodimeric CD8 alpha chains and either gamma/delta or alpha/beta TCR. In RAG-/- mice with a thymus, a similar injection led to complete lymphoid reconstitution, with the additional appearance in the gut of CD4+, CD8 alpha/beta+ or CD4+CD8 alpha/alpha+ IEL, all bearing alpha/beta TCR. In contrast, injection of LN T cells into these mice reconstituted a gut IEL population made of CD4+, CD8 alpha/beta+, or CD4+ CD8 alpha/alpha+ cells, all bearing alpha/beta TCR; CD8 alpha/alpha+ TCR-gamma/delta+ or alpha/beta+ IEL were not observed. These results demonstrate that the thymus and/or thymic-derived peripheral T cells are absolutely required for the generation of CD4+, CD8 alpha/beta+, and CD4+CD8 alpha/alpha+ IEL, which are thus thymus dependent. In contrast, TCR+ CD8 alpha/alpha+ IEL appear in the absence of the thymus, and thus are thymus independent.
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Davani, Dariush, Zeev Pancer, and Michael J. H. Ratcliffe. "Ligation of Surface Ig by Gut-Derived Antigen Positively Selects Chicken Bursal and Peripheral B Cells." Journal of Immunology 192, no. 7 (February 24, 2014): 3218–27. http://dx.doi.org/10.4049/jimmunol.1302395.
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Wu, R., J. An, and C. Wang. "AB0072 THE METABOLITES WERE ALTERED IN PATIENTS WITH RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 1214.2–1215. http://dx.doi.org/10.1136/annrheumdis-2023-eular.1763.
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BackgroundRheumatoid arthritis (RA) is characterized by persistent synovitis and abnormal antibodies production[1].The discovery of follicular helper T cells (Tfh) and follicular regulatory T cells (Tfr) has added a new understanding of the mechanisms of antibody production in RA such as anti-cyclic peptide containing citrulline (anti-CCP) [2]. The gut microbiota-derived metabolites are also important in regulating immune system to balance disease and health. And the altered gut microbiota-derived metabolites had been found in RA patients[3]. However, the relationship between gut microbiota-derived metabolites and Tfr/Tfh cells has not been comprehensively evaluated in RA patients to date, which is the focus of our study.ObjectivesWe detected the gut microbiota-derived metabolites and the expression of Tfr and Tfh cells in new-onset RA patients, and then analyzed the relationship between gut microbiota-derived metabolites and Tfr/Tfh cells.Methods17 patients with new-onset RA from the Second Hospital of Shanxi Medical University were recruited. And 13 sex- and age-match healthy controls (HCs) were enrolled. Fecal samples were collected to determine the gut microbiota-derived metabolites by LC-MS/MS-based nontargeted metabolomic. And blood samples were collected to detect the expression of circulating Tfr and Tfh cells by flow cytometry.ResultsThe fecal metabolite profiles between RA and HC groups were different (Figure 1A, B). There were 61 differential annotated metabolites in RA including 34 metabolites upregulated and 27 metabolites downregulated compared to HCs (Figure 1C, D). The KEGG pathway enrichment analysis of the differentially abundant metabolites showed that there were only four pathways were the main pathways related to RA including biosynthesis of unsaturated fatty acids, arginine biosynthesis, tryptophan metabolism as well as alanine, aspartate and glutamate metabolism (Figure 1E). And eleven differentially abundant metabolites were involved in the four mainly altered pathways.The correlation heatmap of the association of the eleven differentially abundant metabolites with indicators of RA was shown in Figure 2A. It showed that the increased arachidonic acid was positively correlated with DAS28, ESR and anti-CCP.We identified the potential biomarker value of RA by performing receiver operating characteristic (ROC) curve analysis, which showed that arachidonic acid yielded the area under curve (AUC) of 0.724 [95% CI = 0.539-0.909,P=0.038]. It suggested that arachidonic acid was the potential biomarker of RA (Figure 2B). And arachidonic acid was negatively associated with the number of Tfr cells (r=-0.645,P=0.006) and the c-Tfr/c-Tfh ratio (r=-0.623,P=0.009).ConclusionThere was an obvious difference in the fecal metabolite profiles between RA and HCs. Arachidonic acid was identified as the potential biomarker of RA, and the increased arachidonic acid was negatively associated with Tfr cells to affect the disease activity and the production of anti-CCP in RA.References[1]Wu R, Li N, Zhao X, et al. Low-dose Interleukin-2: Biology and therapeutic prospects in rheumatoid arthritis. Autoimmun Rev. 2020, 19(10):102645.[2]Deng J, Wei Y, Fonseca VR, et al. T follicular helper cells and T follicular regulatory cells in rheumatic diseases. Nat Rev Rheumatol. 2019, 15(8):475-90.[3]Chen Y, Ma C, Liu L, et al. Analysis of gut microbiota and metabolites in patients with rheumatoid arthritis and identification of potential biomarkers. Aging (Albany NY). 2021, 13(20):23689-701.Figure 1.(A) The fecal metabolite profiles between RA and HC groups in the positive ion mode were different. (B) The fecal metabolite profiles between RA and HC groups in the negative ion mode were different. (C) The volcano plot showed the differentially altered metabolites. (D) The heatmap of differentially abundant metabolites. (E)The KEGG pathway enrichment analysis of the differentially abundant metabolites.Figure 2:(A) The correlation heatmap of differentially abundant metabolites with indicators of RA. (B)The ROC curve analysis of arachidonic acid.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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Chen, Feidi, Ye Zhao, Xiangsheng Huang, Liang Chen, Mingming Sun, Suxia Yao, Yi Xiao, and Yingzi Cong. "GPR43 mediates microbiota metabolite SCFA induction of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 218.17. http://dx.doi.org/10.4049/jimmunol.198.supp.218.17.
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Abstract As a critical component in maintaining intestinal homeostasis, intestinal epithelial cells (IEC) are known to tune gut microbiota via antimicrobial peptides (AMP) production. In return, microbiota has been reported to regulate IEC expression of AMPs, including RegIIIg and certain defensins. The underlying mechanisms are, however, still not completely understood. The present study attempted to address the novel pathways by which gut microbiota regulates IEC expression of AMP as a way to contribute to intestinal homeostasis. We found that the mice with deficiency of GPR43, a receptor for short chain fatty acids (SCFA), the metabolites of gut microbiota, have lower expression of RegIIIg and b-defensins 1, 3, and 4 in IECs compared to that of WT mice. Oral feeding with SCFA promoted IEC production of both RegIIIg and defensins in mice. Moreover, ex-vivo culture of enteroid revealed that SCFA induction of IEC RegIIIg and b-defensins production is GPR43-dependent. Mechanistically, SCFA activated mTOR and STAT3 in IECs. Knockdown of either mTOR or STAT3 impaired SCFA-induced AMP production. Collectively, our data revealed that microbiota-derived SCFA promote IEC production of both RegIIIg and b-defensins, which is through GPR43 and mediated by mTOR and STAT3 pathways.
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Jin, Linhua, Shinya Kimura, Yixin Zhou, Junya Kuroda, Hiroya Asou, Toshiya Inaba, Takashi Miida, Marina Konopleva, Michael Andreeff, and Yoko Tabe. "The Anti-Proliferative Effects of Tricyclic Coumarin GUT-70 as An Hsp90 Inhibitor In Mantle Cell Lymphoma." Blood 116, no. 21 (November 19, 2010): 3977. http://dx.doi.org/10.1182/blood.v116.21.3977.3977.
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Abstract Abstract 3977 Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor prognosis, requiring novel anticancer strategies. Since p53 inactivating mutations occur primarily in the aggressive and refractory MCL variants, targeting p53-independent signaling pathways is of considerable interest. We previously reported the cytotoxic efficacy of a newly discovered tricyclic coumarin GUT-70 (5-methoxy-2,2-dimethyl-6-(2-methyl-1-oxo-2-butenyl) -10-propyl-2H,8H-benzo[1,2-b;3,4-b ]dipyran-8-one (C23H26O5) (synthesized at Nippon Shinyaku, Kyoto, Japan), originally derived from Calophyllum brasiliense, with more pronounced apoptotic effects in mutant-p53 MCL cells than in wild type-p53 cells (Jin et al., ASH abstract 2009). Some of the coumarin antibiotics are known to bind to chaperone molecule 90-kDa heat shock proteins (Hsp90) and induce degradation of Hsp90 client proteins including key components of multiple signaling pathways for cell proliferation and/or survival. In this study, the mechanisms of action of GUT-70 were investigated in MCL cell lines with known p53 mutation status (wt-p53: JVM-2, Granta-519, mt-p53: Jeko-1, MINO). GUT-70 demonstrated a dose-dependent binding affinity to Hsp90 (competitive binding assay using fluorescently labeled geldanamycin), increased ubiquitinated proteins accumulation, and further induced degradation of Hsp90 client proteins, including cyclin D1, Raf-1, Akt, and mt-p53, or increased Hsp70, a marker of Hsp90 inhibition. The downregulation of constitutively overexpressed cyclin D1 in MCL by GUT-70 was accompanied by p27 accumulation, decreased Rb phosphorylation, and impeded cell cycle progression in the wt-p53 JVM2 and Granta 519. However, GUT-70 induced apoptosis in mt-p53-bearing MINO and Jeko cells which was accompanied by only minimal cell cycle arrest. These findings suggest that apoptosis induction by GUT-70 in mt-p53 cells is in part independent from cell cycle arrest is known to protect cells from apoptosis. Moreover, the mt-p53 depletion by GUT-70 will further diminish its “gain of functions” for cell proliferation and anti-apoptosis. To determine if GUT-70 might potentiate the apoptotic effects of commonly used chemotherapeutic agents, we assessed the combination effects of GUT-70 with bortezomib (BTZ), a selective inhibitor of the 26S proteasome, and with doxoubicin (DOX), a conventional chemotherapeutic agent drug for MCL. Synergistic anti-proliferative effects of GUT-70 and BTZ or GUT-70 and DOX combinations were observed in both wt-p53 and mt-p53 MCL cells at 48 h post-exposure (combination index; GUT-70/Bortezomib; 0.59 for JVM2, 0.73 forMINO, GUT-70/Doxorubicin; 0.37 for JVM2, 0.35 for MINO). In conclusion, our results demonstrate that the novel anticancer agent tricyclic coumarin GUT-70, an Hsp90 inhibitor, has potential utility for mt-p53 bearing MCL cells, and in the combination therapy of MCL. Disclosures: No relevant conflicts of interest to declare.
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KAO, CHENG-YUAN, Cherng-Shyang Chang, Yi-Chu Liao, Chih-Ting Huang, Chiao-Mei Lin, Yi-Ting Tsai, I.-Jung Lin, Jhen-Wei Ruan, and Yu-Chieh Liao. "The Novel Roles of Dusp6 in Gut Barrier Modulation and Microbiome Shaping in a Mouse Colitis Model." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 115.14. http://dx.doi.org/10.4049/jimmunol.208.supp.115.14.
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Abstract Gut microbiota dysbiosis and barrier integrity are important contributors to overall health and many diseases. Our study demonstrated that dual-specificity phosphatase 6 (Dusp6)-depletion is a novel modulator that enhances baseline gut barrier integrity. We found that Dusp6-knockout mice were more resistant to dextran sulfate sodium (DSS)-induced colitis and had enhanced intrinsic colonic tight-junctions and elongated microvilli before exposure to DSS. Our FMT in germ-free mice and co-housing experiments found that the Dusp6-knockout-derived gut microbiota contribute substantially to colitis resistance in mice. Further gut microbiome analysis showed that Dusp6-knockout mice harbored fewer pathobiont facultative anaerobes and more obligate anaerobes than wild-type mice after DSS treatment. Through multi-omics analysis, we found that epithelial barrier integrity and hypoxic and oxygen homeostasis regulation related pathways were more enriched in DUSP6-depleted Caco-2 cells and with a cultivation-based approach, we reported 11 new mouse gut microbiome members. Finally using microbe-phenotype triangulation and mono-colonization of germ-free mice, we found that the newly discovered Duncaniella species contributed to the colitis protection. In sum, identifying functioning gut microbiota members that shape host physiology and disease susceptibility will be vital to the advance of microbiota-based therapeutics. This work was supported by the following grants: IM-108-PP-04 from NHRI and 106-2628-B-400-001-MY3, 106-2923-B-400-001-MY3, 108-2321-B-400-011-, 109-2327-B-400-001-, 109-2320-B-400-008-MY3, 110-2327-B-400-005- from MOST.
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Wu, J. J., J. X. Chen, T. P. Rothman, and M. D. Gershon. "Inhibition of in vitro enteric neuronal development by endothelin-3: mediation by endothelin B receptors." Development 126, no. 6 (March 15, 1999): 1161–73. http://dx.doi.org/10.1242/dev.126.6.1161.
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The terminal colon is aganglionic in mice lacking endothelin-3 or its receptor, endothelin B. To analyze the effects of endothelin-3/endothelin B on the differentiation of enteric neurons, E11-13 mouse gut was dissociated, and positive and negative immunoselection with antibodies to p75(NTR)were used to isolate neural crest- and non-crest-derived cells. mRNA encoding endothelin B was present in both the crest-and non-crest-derived cells, but that encoding preproendothelin-3 was detected only in the non-crest-derived population. The crest- and non-crest-derived cells were exposed in vitro to endothelin-3, IRL 1620 (an endothelin B agonist), and/or BQ 788 (an endothelin B antagonist). Neurons and glia developed only in cultures of crest-derived cells, and did so even when endothelin-3 was absent and BQ 788 was present. Endothelin-3 inhibited neuronal development, an effect that was mimicked by IRL 1620 and blocked by BQ 788. Endothelin-3 failed to stimulate the incorporation of [3H]thymidine or bromodeoxyuridine. Smooth muscle development in non-crest-derived cell cultures was promoted by endothelin-3 and inhibited by BQ 788. In contrast, transcription of laminin alpha1, a smooth muscle-derived promoter of neuronal development, was inhibited by endothelin-3, but promoted by BQ 788. Neurons did not develop in explants of the terminal bowel of E12 ls/ls (endothelin-3-deficient) mice, but could be induced to do so by endothelin-3 if a source of neural precursors was present. We suggest that endothelin-3/endothelin B normally prevents the premature differentiation of crest-derived precursors migrating to and within the fetal bowel, enabling the precursor population to persist long enough to finish colonizing the bowel.
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Masenga, Sepiso K., Joreen P. Povia, Propheria C. Lwiindi, and Annet Kirabo. "Recent Advances in Microbiota-Associated Metabolites in Heart Failure." Biomedicines 11, no. 8 (August 21, 2023): 2313. http://dx.doi.org/10.3390/biomedicines11082313.
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Heart failure is a risk factor for adverse events such as sudden cardiac arrest, liver and kidney failure and death. The gut microbiota and its metabolites are directly linked to the pathogenesis of heart failure. As emerging studies have increased in the literature on the role of specific gut microbiota metabolites in heart failure development, this review highlights and summarizes the current evidence and underlying mechanisms associated with the pathogenesis of heart failure. We found that gut microbiota-derived metabolites such as short chain fatty acids, bile acids, branched-chain amino acids, tryptophan and indole derivatives as well as trimethylamine-derived metabolite, trimethylamine N-oxide, play critical roles in promoting heart failure through various mechanisms. Mainly, they modulate complex signaling pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells, Bcl-2 interacting protein 3, NLR Family Pyrin Domain Containing inflammasome, and Protein kinase RNA-like endoplasmic reticulum kinase. We have also highlighted the beneficial role of other gut metabolites in heart failure and other cardiovascular and metabolic diseases.
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Jedrzkiewicz, Sean, Galina Kataeva, Cory M. Hogaboam, Steven L. Kunkel, Robert M. Strieter, and Derek M. McKay. "Superantigen Immune Stimulation Evokes Epithelial Monocyte Chemoattractant Protein 1 and RANTES Production." Infection and Immunity 67, no. 11 (November 1, 1999): 6198–202. http://dx.doi.org/10.1128/iai.67.11.6198-6202.1999.
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ABSTRACT Bacterial superantigens (SAgs) have been implicated in inflammatory disease, and SAg-treated mice have increased jejunal T cells. Here we show that T84 cells (a human epithelial cell line) display increased MCP-1 and RANTES mRNA expression and protein production in response to conditioned medium from Staphylococcus aureus enterotoxin B (SEB; a model SAg)-activated immune cells. Also, MCP-1 and RANTES mRNAs were increased in jejunal enterocytes isolated from SEB-treated mice. We suggest that T-cell recruitment to the gut following SAg immune activation could be partially due to epithelium-derived chemokines.
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Taham-zadeh, Dariush, Yuan Wu, and Michael Ratcliffe. "Role of antigen in later stages of B cell development (153.20)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 153.20. http://dx.doi.org/10.4049/jimmunol.186.supp.153.20.
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Abstract B cell development occurs in the gut associated lymphoid tissue (GALT) of many mammals and birds. In chickens, the early stages of B cell development, including colonization of bursal follicles, B cell proliferation within bursal follicles and repertoire diversification by gene conversion, are supported by surface Ig receptor related constructs that lack antigen binding capacity. Thus early B cell development requires Ig receptor expression but not sIg ligation. In contrast later stages of bursal development, including cortico-medullary redistribution of B cells and their maintenance after hatch, is not supported by those constructs. The later stages of bursal B cell development occur in the presence of gut derived antigens suggesting the possibility that later stage may require antigen mediated sIg receptor ligation as opposed to simply receptor expression. To address this directly, we have introduced Ig receptor related constructs with defined antigen specificity into developing chick embryos. Expression of such constructs is sufficient to support early stages of B cell development, and in the absence of cognate antigen, is not sufficient to support the later stages of B cell development. Preliminary evidence suggests, however, that introduction of cognate antigen results in extended maintenance of receptor expressing B cells after hatch suggesting that ligation of the BCR may act as a survival signal in the later stages of B cell development in the bursa.
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Muku, Gulsum, Iain Murray, Juan Espín, and Gary Perdew. "Urolithin A Is a Dietary Microbiota-Derived Human Aryl Hydrocarbon Receptor Antagonist." Metabolites 8, no. 4 (November 29, 2018): 86. http://dx.doi.org/10.3390/metabo8040086.
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Urolithins (e.g., UroA and B) are gut microbiota-derived metabolites of the natural polyphenol ellagic acid. Urolithins are associated with various health benefits, including attenuation of inflammatory signaling, anti-cancer effects and repression of lipid accumulation. The molecular mechanisms underlying the beneficial effects of urolithins remain unclear. We hypothesize that some of the human health benefits of urolithins are mediated through the aryl hydrocarbon receptor (AHR). Utilizing a cell-based reporter system, we tested urolithins for the capacity to modulate AHR activity. Cytochrome P450 1A1 (CYP1A1) mRNA levels were assessed by real-time quantitative polymerase chain reaction. Competitive ligand binding assays were performed to determine whether UroA is a direct ligand for the AHR. Subcellular AHR protein levels were examined utilizing immunoblotting analysis. AHR expression was repressed in Caco-2 cells by siRNA transfection to investigate AHR-dependency. UroA and B were able to antagonize 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced AHR-mediated transcriptional activity. Furthermore, UroA and B attenuated TCDD-mediated stimulation of CYP1A1 mRNA levels. In addition, competitive ligand binding assays characterized UroA as a direct AHR ligand. Consistent with other AHR antagonists, UroA failed to induce AHR retention in the nucleus. AHR is necessary for UroA-mediated attenuation of cytokine-induced interleukin 6 (IL6) and prostaglandin-endoperoxide synthase 2 (PTGS2) expression in Caco-2 cells. Here we identified UroA as the first dietary-derived human selective AHR antagonist produced by the gut microbiota through multi-step metabolism. Furthermore, previously reported anti-inflammatory activity of UroA may at least in part be mediated through AHR.
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Simo, P., P. Simon-Assmann, C. Arnold, and M. Kedinger. "Mesenchyme-mediated effect of dexamethasone on laminin in cocultures of embryonic gut epithelial cells and mesenchyme-derived cells." Journal of Cell Science 101, no. 1 (January 1, 1992): 161–71. http://dx.doi.org/10.1242/jcs.101.1.161.
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Previous studies have shown that glucocorticoids accelerate intestinal maturation and that this process is mediated by the mesenchymal cells. The possible involvement of laminin (LN), a basement membrane component, in this mesenchymal mediation has been analyzed. For this purpose, the influence of dexamethasone (DX) on the synthesis of LN, its chain composition and its cellular distribution has been examined biochemically and immunocytochemically in two different mesenchyme-derived cell populations, fetal intestinal mesenchymal cells and fetal skin fibroblasts, as well as in cocultures of intestinal endodermal cells seeded on top of confluent fetal skin fibroblasts. Neither the amount of metabolically labeled LN purified by affinity chromatography (expressed per mg cell proteins), nor the A versus B chain ratio monitored after separation on gel electrophoresis and immunoblotting, showed significant differences after 5 days of DX treatment. However, glucocorticoids induced a shift from secreted to cell-associated LN molecules paralleling a striking difference in the immunostaining pattern of intracellular and surface LN in the mesenchyme-derived cell monocultures; the granular intracytoplasmic LN staining in the control cultures was replaced by a fibrillar organization of LN molecules concomitantly with an increased accumulation at the cell surface. In 2-day DX-treated cocultures, there was an acceleration of LN deposition at the epithelial-fibroblastic interface, which accompanied the enhanced expression of epithelial cell differentiation markers (brush border digestive enzymes). These DX-induced changes can be blocked by the addition of anti-LN antibodies in the culture medium. These findings further support the concept that glucocorticoid action on intestinal epithelial cells involves alterations in the extracellular microenvironment, assessed here for LN molecules, occurring at the level of the mesenchymal cell compartment. These changes may contribute to an accelerated organization of LN at the epithelial-mesenchymal interface and subsequently to epithelial differentiation.
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Lambolez, Florence, Orly Azogui, Anne-Marie Joret, Corinne Garcia, Harald von Boehmer, James Di Santo, Sophie Ezine, and Benedita Rocha. "Characterization of T Cell Differentiation in the Murine Gut." Journal of Experimental Medicine 195, no. 4 (February 11, 2002): 437–49. http://dx.doi.org/10.1084/jem.20010798.
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Gut intraepithelial CD8 T lymphocytes (T-IEL) are distinct from thymus-derived cells and are thought to derive locally from cryptopatch (CP) precursors. The intermediate stages of differentiation between CP and mature T-IEL were not identified, and the local differentiation process was not characterized. We identified and characterized six phenotypically distinct lineage-negative populations in the CP and the gut epithelium: (a) we determined the kinetics of their generation from bone marrow precursors; (b) we quantified CD3-ϵ, recombination activating gene (Rag)-1, and pre-Tα mRNAs expression at single cell level; (c) we characterized TCR-β, -γ, and -α locus rearrangements; and (d) we studied the impact of different mutations on the local differentiation. These data allowed us to establish a sequence of T cell precursor differentiation in the gut. We also observed that the gut differentiation varied from that of the thymus by a very low frequency of pre-Tα chain mRNA expression, a different kinetics of Rag-1 mRNA expression, and a much higher impact of CD3 ϵ/δ and pre-Tα deficiencies. Finally, only 3% of CP cells were clearly involved in T cell differentiation, suggesting that these structures may have additional physiological roles in the gut.
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Fernández-Tomé, Samuel, Alicia C. Marin, Lorena Ortega Moreno, Montserrat Baldan-Martin, Irene Mora-Gutiérrez, Aitor Lanas-Gimeno, José Andrés Moreno-Monteagudo, et al. "Immunomodulatory Effect of Gut Microbiota-Derived Bioactive Peptides on Human Immune System from Healthy Controls and Patients with Inflammatory Bowel Disease." Nutrients 11, no. 11 (October 31, 2019): 2605. http://dx.doi.org/10.3390/nu11112605.
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Bioactive peptides secreted by probiotic Bifidobacterium longum (peptide B7) and opportunistic pathogen Bacteroides fragilis (peptide B12) modulate the intestinal cytokine milieu in health. Here, we characterized their capacity to modulate both the mucosal cytokine production and the phenotype of circulating antigen presenting cells (APCs) in active inflammatory bowel disease (IBD). The IBD mucosa produced higher levels of pro-inflammatory cytokines referred to healthy controls (HCs). Peptides B7 and B12, however, did not ameliorate the mucosal cytokine milieu in IBD. Human circulating APCs (B-cells, monocytes, plasmacytoid dendritic cells (pDCs), and conventional dendritic cells (cDCs)) were characterized by flow cytometry in presence/absence of the peptides. Circulating B-cells, monocytes, and cDCs from IBD patients were more activated than those from HCs. Peptide B7, but not B12, decreased CCR2 expression on all APC subsets from HC, but not IBD patients. Moreover, both peptides tend to further increase their pro-inflammatory profile in IBD. In summary, IBD patients display mucosal and circulating APC pro-inflammatory properties. Peptide B7 immunomodulatory capacity elicited over circulating APCs from HC, but not IBD patients, suggests the presence of disrupted modulatory mechanisms for this peptide in IBD. Future studies should address the effect of bacteria-derived immunomodulatory peptides in non-inflamed (quiescent) IBD patients.
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Trent, Brandon J., Widian Jubair, Sabrina Fetchner, Meagan Chriswell, and Kristine Kuhn. "Promotion of Autoimmune Arthritis via Tryptophan Metabolism and Production of the Bacterial-Derived Tryptophan Metabolite Indole." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 105.12. http://dx.doi.org/10.4049/jimmunol.206.supp.105.12.
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Abstract Dysbiosis of gut bacterial communities in autoimmunity is a noted phenomenon in both murine models and human patients; however, the mechanisms of dysbiosis that promote disease pathogenesis remain unclear. In agreement with such studies, our lab has published that administration of antibiotics to deplete the microbiota late in the course of murine collagen-induced arthritis (CIA) significantly ameliorated disease. To understand the mechanisms by which microbiota depletion would significantly decrease CIA, we analyzed cecal metabolites by LC-MS during CIA and after antibiotic treatment and observed significant changes in various tryptophan metabolite levels. Interestingly, mice placed on a tryptophan-free diet had significantly decreased CIA development and increased in regulatory T cell (Treg) populations in the spleen. Further studies identified increases in indole, a bacterial-derived, tryptophan metabolite that strongly correlated with CIA progression. Direct administration of indole during CIA promoted disease and led to increases in T follicular cell (Tfh) and B cell populations in the peyer’s patches and mesenteric lymph nodes. Ex vivo stimulation of murine splenic B cells with indole resulted in significantly increased IgG production and a ≈10% increase in the frequency of CD23+ B cells. Our results suggest that gut dysbiosis due to CIA results in altered tryptophan metabolism and indole production, which promotes CIA pathogenesis via activation of T and B cell populations and antibody production. Precise understanding of which indole metabolites are involved and how they influence mucosal and systemic immune responses will help elucidate the role of intestinal dysbiosis in autoimmunity.
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Bellezzo, J. M., R. S. Britton, B. R. Bacon, and E. S. Fox. "LPS-mediated NF-kappa beta activation in rat Kupffer cells can be induced independently of CD14." American Journal of Physiology-Gastrointestinal and Liver Physiology 270, no. 6 (June 1, 1996): G956—G961. http://dx.doi.org/10.1152/ajpgi.1996.270.6.g956.
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Lipopolysaccharide (LPS) activation of macrophages occurs after LPS complexed with serum LPS-binding protein (LBP) binds CD14. Activation of the nuclear transcription factor NF-kappa B is directly related to this event. Since the role of CD14 in LPS signaling has not been evaluated in Kupffer cells, the resident hepatic macrophage, the purpose of this study was to characterize LPS-mediated NF-kappa B activation under CD14-dependent (1% serum, as a source of LBP) and CD14-independent (serum-free) conditions. Classic CD14-dependent signaling was seen in peritoneal macrophages where serum potentiated NF-kappa B activation. However, in Kupffer cells, NF-kappa B was activated by LPS under CD14-independent conditions, and this response was not potentiated by serum. The activation of NF-kappa B in Kupffer cells, by 1 ng/ml LPS, reached a maximum within 60 min of stimulation. However, peritoneal macrophage NF-kappa B activation occurred only in serum and increased progressively through 240 min of stimulation. These results suggest a novel mechanism of LPS-mediated activation in Kupffer cells that may represent an adaptation to their role in clearance and detoxification of gut-derived endotoxin.
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Maybaum, T. A., and J. D. Reynolds. "B cells selected for apoptosis in the sheep ileal Peyer's patch have enhanced mutational diversity in the Ig V lambda light chain." Journal of Immunology 157, no. 4 (August 15, 1996): 1474–84. http://dx.doi.org/10.4049/jimmunol.157.4.1474.
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Abstract To investigate the molecular events associated with B cell apoptosis, we analyzed follicular B cells from the large Peyer's patch (PP) in the sheep ileum. Over 95% of B cells generated in the ileal PP are rapidly destroyed by apoptosis. Ig V lambda sequences from apoptotic B cells were compared with sequence from B cells about to emigrate from the PP. The sequences originated from two germline genes, V lambda 5.1 and V lambda 5.3. Only V lambda 5.1 was rearranged in apoptotic cells, whereas both V lambda 5.1 and V lambda 5.3 were rearranged in B cells about to emigrate. Apoptotic B cells had evidence of increased Ig sequence diversity based on: 1) significantly greater replacement to silent mutation ratios in the complementarity determining regions, 2) the more random distribution of mutations, and 3) the lack of mutational specificity compared with the mutational bias favoring transitions and purines in B cells about to emigrate. Based on this analysis, we propose that the continual proliferation of B cells in the PP follicle might increase their affinity to local Ags. Those Ags that are sequestered in this environment might be expected to stimulate the production of B cells with such high-affinity receptors that ligation would trigger apoptosis. This could account for the deletion of B cells with specificity for self-antigens, selecting ligands as well as gut-derived food and microbial Ags. This process could contribute to the elimination of self-reactive B cells, the expansion of the antibody repertoire, and the generation of oral tolerance.
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Tu, Zhengkun, Adel Bozorgzadeh, Robert H. Pierce, Jonathan Kurtis, I. Nicholas Crispe, and Mark S. Orloff. "TLR-dependent cross talk between human Kupffer cells and NK cells." Journal of Experimental Medicine 205, no. 1 (January 14, 2008): 233–44. http://dx.doi.org/10.1084/jem.20072195.
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The liver protects the host from gut-derived pathogens yet is tolerant of antigenic challenge from food and commensal sources. Innate responses involving liver macrophages (Kupffer cells) and effector liver natural killer (NK) cells form the first line in this defense. We address the impact of Toll-like receptor (TLR) signaling on the cross talk between these two cells, and reveal how the liver displays a down-regulated inflammatory response to constitutive bacterial elements through the secretion of interleukin (IL) 10 yet retains a vigorous response to viral challenge. The data support the model that (a) human liver Kupffer cells respond to TLR ligands and indirectly activate NK cells; (b) the activation depends on cell–cell contact; (c) the Kupffer cells synthesize NK cell activating signals, among which IL-18 is critical, and NK cell inhibitory factors, including IL-10; (d) ligands that signal via myeloid differentiation factor 88 induce IL-10, giving a blunted response in the NK cells; and (e) ligands that signal via the Toll–IL-1 receptor domain–containing adaptor inducing interferon (IFN) β–IFN regulatory factor 3 pathway induce less IL-10, and also directly potentiate the stimulatory effect of IL-18 on NK cells, resulting in enhanced activation. Subversion of cellular mechanisms of innate immune response against viruses may be important for hepatotropic viruses (e.g., hepatitis B and C) to develop persistence.
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Jin, Linhua, Shinya Kimura, Yixin Zhou, Junya Kuroda, Hiroya Asou, Toshiya Inaba, Michael Andreeff, Takashi Miida, and Yoko Tabe. "The Tricyclic Coumarin GUT-70 Induces Apoptosis and Cell Cycle Arrest Preferentially in Mantle Cell Lymphomas with Mutant p53." Blood 114, no. 22 (November 20, 2009): 1684. http://dx.doi.org/10.1182/blood.v114.22.1684.1684.
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Abstract Abstract 1684 Poster Board I-710 Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma resistant to standard chemotherapy. Since p53 inactivating mutations occur primarily in the aggressive and refractory MCL variants, development of novel compounds that target p53-independent signaling pathways is of considerable interest. We investigated the cytotoxic efficacy and molecular mechanisms of a newly discovered anticancer agent GUT-70 (synthesized at Nippon Shinyaku, Kyoto, Japan), a natural product derived from the stem bark of Calophyllum brasiliense, characterized as a tricyclic coumarin with the formula 5-methoxy-2,2-dimethyl-6-(2-methyl-1-oxo-2-butenyl) -10-propyl-2H,8H-benzo[1,2-b;3,4-b]dipyran-8-one (C23H26O5). This agent has pronounced anti-tumor activity, but does not inhibit colony formation by normal hematopoietic progenitors or proliferation of normal human hepatocytes. (Kimura, Int J Cancer 2005;113:158) However, their mechanisms have not been fully investigated. In this study, cytotoxicity and mechanisms of action of GUT-70 were investigated in MCL cell lines with wild-type and mutant p53 (wt-p53: JVM-2, Granta-519, mt-p53: Jeko-1, MINO). Treatment with GUT-70 resulted in marked reduction in cell growth (trypan blue corrected cell numbers) and an increase in the apoptotic fraction (Annexin V), in a time- and concentration-dependent manner. Importantly, mt-p53 MCL were more sensitive than wt-p53 cells (IC50 at 48 hrs: JVM-2, 4.5 μM; Granta 519, 6.3 μM; Jeko-1, 0.7 μM; MINO, 2.2 μM, % specific apoptosis of 5μM GUT-70 treated cell: JVM-2, 18.5%; Granta 519, 17.6%; Jeko-1, 38.1%; MINO, 30.9%; Annexin V). GUT-70 also impeded cell cycle progression, resulting in a decreased S-phase with increased G0/G1 cells independent of p53 status (S-phase was decreased by 8.2 % in JVM-2, 12.1% in Granta 519, 10.0 % in Jeko-1, 9.8 % in MINO). This was associated with a dramatic morphological change: bleb-like cytoplasmic enlargement without visible nuclear breakdown observed by phase-contrast time-lapse video microscopy. Next, the ability of GUT-70 to modulate cell cycle and apoptosis related proteins including p53 target genes was analyzed by western blotting. GUT-70 treatment significantly reduced cyclin D1, the hallmark of MCL, believed to be critical for lymphomagenesis, and increased p27 levels. Furthermore, GUT-70 inactivated and/or degraded Rb and repressed E2F1, effects similar to the action of the specific 26S proteasome inhibitors MG132 and bortezomib. GUT-70 induced mitochondrial apoptosis associated with caspase-9 and -3 activation, accompanied by transcriptional induction of the proapoptotic BH3-only protein Noxa. Notably, in highly sensitive Jeko-1 and MINO cells expressing mt-TP53, antiapoptotic Mcl-1 was not upregulated, whereas in less sensitive JVM-2 and Granta-519 cells with wt-TP53 GUT-70 caused Mcl-1 accumulation, which co-immunoprecipitated with Noxa. In addition, we observed higher levels of activated Bak in Jeko-1 and MINO cells compared to JVM-2 and Granta-519 cells. In summary, these data indicate that the novel anticancer agent GUT-70 depletes cyclin D1 and induces mitochondrial apoptotic cell death in MCL. Notably, these effects are more pronounced in MCL with mutant p53, a known negative prognostic factor for MCL. These findings suggest potential utility of GUT-70 for the treatment of MCL. Disclosures No relevant conflicts of interest to declare.
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Berkowska, Magdalena A., Gertjan J. A. Driessen, Vasilis Bikos, Christina Grosserichter-Wagener, Kostas Stamatopoulos, Andrea Cerutti, Bing He, et al. "Human memory B cells originate from three distinct germinal center-dependent and -independent maturation pathways." Blood 118, no. 8 (August 25, 2011): 2150–58. http://dx.doi.org/10.1182/blood-2011-04-345579.
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Abstract Multiple distinct memory B-cell subsets have been identified in humans, but it remains unclear how their phenotypic diversity corresponds to the type of responses from which they originate. Especially, the contribution of germinal center-independent responses in humans remains controversial. We defined 6 memory B-cell subsets based on their antigen-experienced phenotype and differential expression of CD27 and IgH isotypes. Molecular characterization of their replication history, Ig somatic hypermutation, and class-switch profiles demonstrated their origin from 3 different pathways. CD27−IgG+ and CD27+IgM+ B cells are derived from primary germinal center reactions, and CD27+IgA+ and CD27+IgG+ B cells are from consecutive germinal center responses (pathway 1). In contrast, natural effector and CD27−IgA+ memory B cells have limited proliferation and are also present in CD40L-deficient patients, reflecting a germinal center-independent origin. Natural effector cells at least in part originate from systemic responses in the splenic marginal zone (pathway 2). CD27−IgA+ cells share low replication history and dominant Igλ and IgA2 use with gut lamina propria IgA+ B cells, suggesting their common origin from local germinal center-independent responses (pathway 3). Our findings shed light on human germinal center-dependent and -independent B-cell memory formation and provide new opportunities to study these processes in immunologic diseases.
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Kapur, R. P., D. A. Sweetser, B. Doggett, J. R. Siebert, and R. D. Palmiter. "Intercellular signals downstream of endothelin receptor-B mediate colonization of the large intestine by enteric neuroblasts." Development 121, no. 11 (November 1, 1995): 3787–95. http://dx.doi.org/10.1242/dev.121.11.3787.
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Mice homozygous for the piebald lethal (sl) mutation, which have a complete deletion of endothelin receptor-B, fail to form ganglion cells in the distal large intestine and are nearly devoid of cutaneous melanocytes. These phenotypic features stem from incomplete colonization of the hindgut and skin by neural crest-derived neuroblasts and melanoblasts, respectively. We have used expression of a transgene, dopamine-beta-hydroxylase-nlacZ, to study colonization of the enteric nervous system in sl/sl embryos and sl/sl <--> wild-type chimeric mice. Enteric neuroblasts derived from the vagal neural crest colonize the developing foregut, midgut and distal small intestine of sl/sl embryos in a cranial-to-caudal manner indistinguishable from sl/+ or +/+ embryos. However, colonization of the large intestine is retarded and the distal large intestine is never colonized, a developmental defect identical to that observed in lethal spotted (endothelin-3 deficient) embryos. The coat pigmentation and relative distributions of mutant and wild-type ganglion cells in sl/sl <--> wild-type chimeras indicate that the defect associated with endothelin receptor-B gene deletion is not strictly neuroblast autonomous (independent of environmental factors). Instead, intercellular interactions downstream of the endothelin receptor-B mediate complete colonization of the skin and gut by neural crest cells.
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González-Sarrías, Antonio, Mar Larrosa, Francisco Abraham Tomás-Barberán, Piero Dolara, and Juan Carlos Espín. "NF-κB-dependent anti-inflammatory activity of urolithins, gut microbiota ellagic acid-derived metabolites, in human colonic fibroblasts." British Journal of Nutrition 104, no. 4 (March 26, 2010): 503–12. http://dx.doi.org/10.1017/s0007114510000826.
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Previous studies have reported the anti-inflammatory properties of pomegranate extracts, suggesting that ellagitannins (ET) and ellagic acid (EA) are the main anti-inflammatory compounds. However, both ET and EA are metabolised in vivo by the gut microbiota to yield urolithins (Uro) which can be found in the gut and in systemic bloodstream. The present study was carried out to evaluate the individual effect of EA and their microbiota-derived metabolites Uro on colon fibroblasts upon IL-1β treatment as an in vitro inflammation model. Uro-A and Uro-B (10 μm) inhibited PGE2 production (85 and 40 %, respectively) after IL-1β stimulation, whereas EA did not show any effect. Uro-A, but not Uro-B, down-regulated cyclo-oxygenase-2 (COX-2) and microsomal PGE synthase-1 (mPGES-1) mRNA expression and protein levels. Both Uro inhibited NF-κB translocation to nucleus. Slight but significant effects were found in the activation of mitogen-activated protein kinase (MAPK) pathways. Uro-A lowered c-Jun N-terminal kinase phosphorylation state, and both Uro inhibited p38 activation. No metabolites derived from Uro or EA were found in the cell media upon incubation of EA or Uro with the cells, and only traces of the compounds were found inside the cells. The present results suggest that Uro, mainly Uro-A, are the main compounds that are responsible for the pomegranate anti-inflammatory properties. The mechanism of action implicated seems to be via the inhibition of activation of NF-κB and MAPK, down-regulation of COX-2 and mPGES-1 expressions, and consequently,via the reduction of PGE2 production. Taking into account that Uro did not enter the cells, a competitive binding for IL-1β membrane receptor cannot be discarded.
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Vinderola, Gabriel, Gabriela Perdigón, Jairo Duarte, Edward Farnworth, and Chantal Matar. "Effects of the oral administration of the products derived from milk fermentation by kefir microflora on immune stimulation." Journal of Dairy Research 73, no. 4 (July 7, 2006): 472–79. http://dx.doi.org/10.1017/s002202990600197x.
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Nutritional status has a major impact on the immune system. Probiotic effects ascribed to fermented dairy products arise not only from whole microorganisms but also from metabolites (peptides, exopolysaccharides) produced during the fermentation. We recently demonstrated the immunomodulating capacity of kefir in a murine model. We now aimed at studying the immunomodulating capacity in vivo of the products derived from milk fermentation by kefir microflora (PMFKM) on the gut. BALB/c mice received the PMFKM for 2, 5 or 7 consecutive days. IgA+ and IgG+ cells were determined on histological slices of the small and large intestine. IL-4, IL-6, IL-10, IL-12, IFNγ and TNFα were determined in the gut, intestinal fluid and blood serum. IL-6 was also determined in the supernatant of a primary culture of small intestine epithelial cells challenged with PMFKM. PMFKM up-regulated IL-6 secretion, necessary for B-cell terminal differentiation to IgA secreting cells in the gut lamina propria. There was an increase in the number of IgA+ cells in the small and large intestine. The increase in the number of IgA+ cells was accompanied by an increase in the number of IL-4+, IL-10+ and IL-6+ cells in the small intestine. Effects of PMFKM in the large intestine were less widely apparent than the ones observed at the small intestine lamina propria. All cytokines that increased in the small intestine lamina propria, also did so in blood serum, reflecting here the immunostimulation achieved in the gut mucosa. We observed that the PMFKM induced a mucosal response and it was able to up and down regulate it for protective immunity, maintaining the intestinal homeostasis, enhancing the IgA production at both the small and large intestine level. The opportunity exists then to manipulate the constituents of the lumen of the intestine through dietary means, thereby enhancing the health status of the host.
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Rahal, Zahraa, Fuduan Peng, Yuejiang Liu, Matthew C. Ross, Ansam Sinjab, Ke Liang, Jiping Feng, et al. "Abstract 2883: Gut microbiome dysbiosis promotes immune suppression and lung cancer development." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2883. http://dx.doi.org/10.1158/1538-7445.am2023-2883.
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Abstract Mounting evidence supports synergistic roles for the gut microbiome in cancer progression. Yet, the interplay between the gut microbiome and immune responses in cancer is still poorly understood. We recently showed that gut microbiome changes are closely associated with development of Kras-mutant lung adenocarcinoma (KM-LUAD) in a human-relevant, tobacco-associated mouse model (Gprc5a-/-; G). Knockout of the antimicrobial protein Lcn2 in these mice (Gprc5a-/-/Lcn2-/-; GL) further reduced microbial diversity while enhancing inflammation and tumor development. We thus hypothesized that microbial dysbiosis in the gut, such as that incurred by loss of Lcn2, may exacerbate LUAD development. Here, we investigated the effects of gut microbiome modulation on LUAD pathogenesis using fecal microbiota transfer (FMT) in both syngeneic and tobacco carcinogenesis models. Syngeneic G mice (transplant of G LUAD cells) that received FMT from GL donors (G < GL) exhibited significantly increased tumor growth relative to littermates with FMT from G mice (G < G). These effects were recapitulated in an independent syngeneic model (KrasG12D LKR13 cells in wild type mice). Tobacco carcinogen-exposed G < GL mice also exhibited increased lung tumor development compared with similarly exposed G < G littermates. 16S rDNA-Seq analysis of fecal pellets revealed significant differences in gut beta diversity between syngeneic G < G and G < GL mice. G < GL mice additionally displayed elevated relative abundance of tumor-promoting Alistipes, while Ruminoccocus and Akkermansia, taxa associated with favorable response to immunotherapy, were reduced. We next performed single-cell RNA-sequencing to comprehensively probe the tumor immune microenvironment (TIME) and the immune milieu near the gut of tumors and mesenteric lymph nodes (MLNs), respectively. The TIME in G < GL mice displayed an overall enhanced immunosuppressive phenotype evidenced by prominently increased fractions of T regulatory and Cd4+ Izumo1r+ exhausted T cells and, conversely, reduced levels of activated Isg15+ Cd8a+ T cells. MLNs from G < GL mice showed markedly increased fractions of memory B cells expressing the immunosuppressor Bank1 and reduced levels of follicular B cells and Cd8a+ Clec9a+ class 1 dendritic cells (cDC1). Flow cytometry further showed enhanced immunosuppression in G < GL relative to G < G mice, including increased fractions of myeloid-derived suppressor cells in the TIME of the former group. Our findings show that gut microbiome dysbiosis fosters lung cancer development by promoting immunosuppression, perhaps via a local and systemic gut microbiota-immune system crosstalk. Modulating the gut microbiome may be a promising strategy for interception or early treatment of lung cancer. Citation Format: Zahraa Rahal, Fuduan Peng, Yuejiang Liu, Matthew C. Ross, Ansam Sinjab, Ke Liang, Jiping Feng, Chidera O. Chukwuocha, Manvi Sharma, Elizabeth Tang, Camille Abaya, Joseph Petrosino, Junya Fujimoto, Seyed Javad Moghaddam, Linghua Wang, Kristi L. Hoffman, Humam Kadara. Gut microbiome dysbiosis promotes immune suppression and lung cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2883.
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Wang, Haiguang, Fanta Barrow, Kira Florczak, Maya Abujamra, Preethy Parthiban, Gavin Fredrickson, and Xavier S. Revelo. "T Follicular Helper Cells Restrain Obesity-Related Metabolic Disease by Damping Intestinal Inflammation." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 64.01. http://dx.doi.org/10.4049/jimmunol.210.supp.64.01.
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Abstract The intestinal immune system is a central modulator of obesity-associated metabolic disease. Particularly, high-affinity intestinal IgA maintains gut homeostasis after its generation in a germinal center (GC) response that requires functional T follicular helper (Tfh) cells in Peyer’s patches (PP). The objective of this study was to determine how obesity affects Tfh function leading to metabolic disease. We investigated the phenotype of Tfh cells in diet-induced obese mice. Obese mice showed enlarged PP featured by an expansion of CXCR5 highICOS highTfh cells. Surprisingly, intestinal Tfh cells in obese mice showed evidence of dysfunction as they expressed substantially lower PD1 and BCL6 but higher CCR7. As a result, the GC response and the generation of IgA +B cells are also defective in obese mice. To determine if Tfh directly regulate intestinal inflammation and metabolic disease during obesity, we fed Tfh-deficient (Cd4 CreBcl6 flox) mice a western diet and investigated their microbiota composition, barrier integrity, and inflammatory status. In the gut, Tfh-deficient obese mice showed a disturbed microbiota, reduced regulatory T cells (Tregs), compromised intestinal barrier, and a loss of the microbiota-derived short-chain fatty acid butyrate. Moreover, we observed exacerbated liver inflammation in Tfh-deficient mice, suggesting a fundamental role for Tfh in dampening inflammation in the gut-liver axis. Mechanistically, Tfh cells express lower levels of insulin receptors and increased Foxo1, suggesting that reduced insulin signaling underlies the dysfunction of Tfh cells during obesity. Overall, our findings highlight an unexpected role for Tfh cells as essential regulators of obesity-related metabolic disease.
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Krämer, S., A. Schimpl, and T. Hünig. "Immunopathology of interleukin (IL) 2-deficient mice: thymus dependence and suppression by thymus-dependent cells with an intact IL-2 gene." Journal of Experimental Medicine 182, no. 6 (December 1, 1995): 1769–76. http://dx.doi.org/10.1084/jem.182.6.1769.
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Interleukin (IL) 2-deficient mice develop a fatal immunopathology characterized by lymphoadenopathy, splenomegaly, T cell infiltration of the bone marrow, loss of B cells, anemia, and inflammation of the gut. The thymus dependence of these disease symptoms was tested by introducing the IL-2 mutation into athymic mice. With the exception of an increase in CD8+ intrahepatic alpha/beta T cells, IL-2 deficiency had no detectable effect on leukocyte composition or health of athymic mice, indicating a key role for thymus-derived T cells in the initiation of disease and demonstrating that B cell development and survival are independent of IL-2. In adoptive transfer studies, lymph node and spleen cells from euthymic IL-2-deficient mice induced disease in athymic mice with an intact IL-2 gene, suggesting that thymus-independent IL-2-expressing cells are unable to control the development of immune pathology. Both IL-2+ and IL-2-/- bone marrow cells repopulated the thymus and the peripheral T cell compartment of the recombination activator gene 2-deficient recipients, and chimeras that had received IL-2-deficient bone marrow developed immune pathology. Disease development was, however, fully or at least partially prevented when 30% of the bone marrow inoculum was derived from mice able to express IL-2. These results demonstrate that the IL-2 deficiency syndrome depends on the intrathymic differentiation of T cells carrying the IL-2 mutation, and that the abnormal activation of IL-2-deficient lymphocytes can be controlled by thymus-derived but not thymus-independent lymphocytes.
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Bhattarai, Chacchu, Phanindra Prasad Poudel, Arnab Ghosh, and Sneha Guruprasad Kalthur. "The <i>RET</i> gene encodes RET protein, which triggers intracellular signaling pathways for enteric neurogenesis, and <i>RET</i> mutation results in Hirschsprung's disease." AIMS Neuroscience 9, no. 1 (2022): 128–49. http://dx.doi.org/10.3934/neuroscience.2022008.
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<abstract> <p>Enteric neurons and ganglia are derived from vagal and sacral neural crest cells, which undergo migration from the neural tube to the gut wall. In the gut wall, they first undergo rostrocaudal migration followed by migration from the superficial to deep layers. After migration, they proliferate and differentiate into the enteric plexus. Expression of the Rearranged During Transfection (<italic>RET</italic>) gene and its protein RET plays a crucial role in the formation of enteric neurons. This review describes the molecular mechanism by which the <italic>RET</italic> gene and the RET protein influence the development of enteric neurons. Vagal neural crest cells give rise to enteric neurons and glia of the foregut and midgut while sacral neural crest cells give rise to neurons of the hindgut. Interaction of RET protein with its ligands (glial cell derived neurotrophic factor (GDNF), neurturin (NRTN), and artemin (ARTN)) and its co-receptors (GDNF receptor alpha proteins (GFRα1-4)) activates the Phosphoinositide-3-kinase-protein kinase B (PI3K-PKB/AKT), RAS mitogen-activated protein kinase (RAS/MAPK) and phospholipase Cγ (PLCγ) signaling pathways, which control the survival, migration, proliferation, differentiation, and maturation of the vagal and sacral neural crest cells into enteric neurons. Abnormalities of the <italic>RET</italic> gene result in Hirschsprung's disease.</p> </abstract>
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Riccardi, Carol, and David W. Pascual. "Head and Neck Lymph Node (HNLN) B Cells from L-Selectin−/− (L-Sel−/−) Mice Show αE Expression Independent of Cholera Toxin (CT) Exposure (41.9)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S31. http://dx.doi.org/10.4049/jimmunol.178.supp.41.9.
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Abstract Oral immunization with soluble protein plus adjuvant stimulates excellent regional, but not distal Ab responses. Although low level expression of distal immune B cells is observed, these wane with time. Studies examining homing receptor expression should provide insight into understanding how distal mucosal immunity is maintained. Studies showed that B lymphocyte trafficking in the HNLN and NALT is L-Sel-dependent. However, the absence of L-Sel enhanced distal B cell maintenance following oral CT immunization of L-Sel−/− mice and was partly compensated by increased αEβ7+ B cells, as evident by the significantly increased IgA antibody-forming cells (AFC) in L-Sel−/− nasal passages (NP) when compared to B6 NP. These IgA responses were supported by elevated HNLN IgA AFC responses (10- to 100-fold greater), and these AFC endured beyond 42 days, but not in B6 mice. To discern whether αEβ7 expression was influenced by CT directly, naive HNLN, mesenteric LN (MLN), and Peyer’s patches (PP) were isolated and stimulated in vitro with LPS, LPS + CT, Con A, or media. The mitogen-stimulated L-Sel−/− HNLN, MLN, and PP B cells showed early expression of αEβ7 at 48 hrs, but by 96 hrs, the L-Sel−/− HNLN clearly showed the greatest levels (30–35%) of αEβ7+ B cells. Both unstimulated and stimulated HNLN B cells showed similar levels of αEβ7 expression, and CT did not enhance αEβ7 expression. MLN and PP showed fewer (~10%) αEβ7+ B cells, and B6 B cells from each tissue showed <10% αEβ7+ B cells. These studies show that αEβ7 compensates for the absence of L-Sel on B cells, and these B cells are mostly derived from HNLN, and not from the gut. Supported by NIH AI-55563.
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Iwata, N., T. Murayama, Y. Matsumori, M. Ito, A. Nagata, T. Taniguchi, K. Chihara, Y. Matsuo, J. Minowada, and T. Matsui. "Autocrine loop through cholecystokinin-B/gastrin receptors involved in growth of human leukemia cells." Blood 88, no. 7 (October 1, 1996): 2683–89. http://dx.doi.org/10.1182/blood.v88.7.2683.bloodjournal8872683.
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The cholecystokinin (CCK)-B/gastrin receptor binds two brain-gut hormones, CCK and gastrin, with high affinities. These peptides have a trophic effect on gastrointestinal cells expressing the receptor in vivo as well as in vitro. Recently, this receptor mRNA was reported to be expressed in immunocytes localized in the lamina propria of normal rat stomach mucosa. Here, we studied the receptor expression in human hematopoietic cells in order to determine whether they play a role in cell growth. The CCK-B/gastrin receptor mRNA was detectable in the polymorphonuclear (PMN) cells but not in the mononuclear cells of normal peripheral white blood cells by reverse transcription-polymerase chain reaction. The receptor transcript was, however, expressed in human leukemia cell lines (14 of 18 cell lines tested) derived from not only myeloid, but also T- and B-lymphoid lineages. The CCK-B/gastrin receptors on several leukemia cell lines were shown to be biologically active by demonstrating ligand-dependent cell proliferation in serum-deprived medium. Interestingly, a human CCK-B/gastrin receptor specific antagonist, YM022, but not its stereotype isoform, selectively inhibited the DNA synthesis of THP-1, MOLT-16, MOLT-14, and CCRF-CEM in the absence of exogenous peptide ligands. Further investigation revealed that these leukemia cell lines and normal PMN cells also expressed gastrin mRNA. These results suggest that growth of human leukemia cells is promoted by an autocrine mechanism through the CCK-B/gastrin receptors.
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Bao, Bin, Youyuan Wang, Pavl Boudreau, Xinyang Song, Meng Wu, Xi Chen, Izabel Patik, et al. "BACTERIAL SPHINGOLIPIDS EXACERBATE COLITIS BY INHIBITING ILC3-DERIVED IL-22 PRODUCTION." Inflammatory Bowel Diseases 30, Supplement_1 (January 25, 2024): S63. http://dx.doi.org/10.1093/ibd/izae020.133.
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Abstract Commensal bacteria of the Bacteroidetes phylum are the primary producers of sphingolipids in the gut lumen. These lipids serve dual roles as bacterial virulence factors and regulators of the host mucosal immune system, including regulatory T cells and invariant natural killer T cells (iNKT). Sphingolipid composition is significantly altered in fecal samples of patients with inflammatory bowel disease (IBD). However, the specific mechanisms by which bacterial sphingolipids modulate mucosal homeostasis and regulate intestinal inflammation remain unclear. In this study, we investigated the impact of bacterial sphingolipids on intestinal inflammation by mono-colonizing mice with Bacteroides fragilis strains that either express or lack sphingolipids during DSS-induced colitis. We discovered that B. fragilis sphingolipids exacerbate intestinal inflammation. Mice mono-colonized with B. fragilis lacking sphingolipids exhibited less severe DSS-induced colitis. This amelioration of colitis was associated with increased production of interleukin-22 (IL-22) by innate lymphoid cell type 3 (ILC3). Consistent with the inhibitory effect of sphingolipids on IL-22 production, mice colonized with B. fragilis lacking sphingolipids showed enhanced epithelial STAT3 activity, intestinal cell proliferation, and antimicrobial peptide production following DSS treatment compared to those colonized with B. fragilis producing sphingolipids. Additionally, colitis severity in mice colonized with B. fragilis lacking sphingolipids was exacerbated upon IL-22 blockade. Furthermore, our study reveals that bacterial sphingolipids restrict epithelial IL-18 production following DSS treatment and interfere with IL-22 production by a subset of ILC3 cells expressing both the interleukin-18 receptor (IL-18R) and major histocompatibility complex class II (MHC II). These findings indicate that B. fragilis-derived sphingolipids exacerbate mucosal inflammation by impeding epithelial IL-18 expression, resulting in compromised production of IL-22 by ILC3 cells. Work Model
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Hedges, Jodi F., Kerri M. Rask, and Mark A. Jutila. "Enhanced immunity following ingestion of plant derived polysaccharides (134.87)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 134.87. http://dx.doi.org/10.4049/jimmunol.182.supp.134.87.
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Abstract Considering the recent increased interest in dietary supplements by the public, characterization of their mechanisms and safety are warranted. Yamoa(tm), bark from the Funtumia elastica tree, has anecdotal positive effects in asthma patients. We have determined that polysaccharide components of Yamoa(tm) and other dietary supplements stimulate innate immunity similarly to LPS, in part by affecting γδ T cells. We hypothesized that orally administered Yamoa(tm) would effectively target this mucosal T cell subset and result in changes in peripheral and tissue-associated immune cells, and provide benefit in mucosal disease settings. Increases in an inflammatory subset of γδ T cells, and B cells were detected in peripheral blood in bovine calves fed Yamoa(tm). Cannulation of the efferent lymphatic ducts of the gut in calves was used to analyze the responses of tissue-derived cells after ingestion of Yamoa(tm). Therapeutic treatment of mice by i.p. injection of Yamoa(tm) and its derived polysaccharides was effective in reduction of fecal CFUs in a mouse model of Salmonella-induced enterocolitis. Interestingly, whereas long term ingestion of low doses of polysaccharides had neutral or negative effects on CFUs in this model, a single prophylactic oral dose of Yamoa(tm) resulted in decreased CFUs. These data suggest that the practical and relevant route of ingestion of plant-derived polysaccharides can affect innate immunity.
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Abraham, Ninan, Daniel Patton, Adam Plumb, Stephen Redpath, Lisa Osborne, and Georgia Perona-Wright. "The development and survival but not function of follicular B cells is dependent on IL-7Rα Tyr449 signaling. (CCR1P.242)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 48.2. http://dx.doi.org/10.4049/jimmunol.192.supp.48.2.
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Abstract IL-7 is a critical cytokine for lymphocyte development but its role in B cells is less well characterized. Using a knock-in mouse with a Tyr to Phe mutation at position 449 (IL-7Rα449F/449F mice) within the cytoplasmic domain of IL-7Rα, we evaluated the role of this YxxM motif in spleen B cells. IL-7Rα449F/449F mice had reduced numbers and increased death of follicular B cells compared to WT, but had significantly more follicular cells than IL-7Rα-/-. The death of IL-7Rα449F/449F follicular cells was not due to a failure to respond to BAFF or lower levels of BAFF. Marginal zone B cells were unaffected in IL-7Rα449F/449F mice. A role for TSLP was ruled out, as TSLPR-/- mice had an identical B cell phenotype to wild-type mice. Bone marrow chimeras and the absence of IL-7Rα on B cells suggested that IL-7 did not directly regulate mature B cells, but that an IL-7-responsive cell was influencing B cells. IL-7 was also critical at the checkpoint between the T1 and T2 stages in the spleen. We tested the functional responses of IL-7Rα449F/449F mice and found no difference in antibody responses to T-dependent or T-independent antigens, or to Influenza/A. IL-7 was important for generation of antibody responses to the intestinal worm H. polygyrus and for naive levels of IgA. Our data shows that IL-7 regulates follicular B cell numbers and survival in a cell-extrinsic manner, via a bone-marrow derived cell, but is not critical for antibody production outside the gut.
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Senizza, Alice, Maria Luisa Callegari, Biancamaria Senizza, Andrea Minuti, Gabriele Rocchetti, Lorenzo Morelli, and Vania Patrone. "Effects of Linoleic Acid on Gut-Derived Bifidobacterium breve DSM 20213: A Transcriptomic Approach." Microorganisms 7, no. 12 (December 17, 2019): 710. http://dx.doi.org/10.3390/microorganisms7120710.
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Bacterial production of conjugated linoleic acid (CLA) has recently received great attention because of the potential health benefits of this fatty acid. Linoleic acid (LA) can be converted to CLA by several microorganisms, including bifidobacteria, possibly as a detoxification mechanism to avoid the growth inhibition effect of LA. In the present in vitro study, we investigated the gene expression landscape of the intestinal strain Bifidobacterium breve DSM 20213 when exposed to LA. Transcriptomic analysis using RNA-seq revealed that LA induced a multifactorial stress response in the test strain, including upregulation of genes involved in iron uptake and downregulation of genes involved in sugar and oligopeptide transport. We also observed reduced transcription of genes involved in membrane and pili biosynthesis. The upregulation of iron uptake was not related to any putative ability of LA to chelate Fe2+, but was somewhat linked to stress response. Furthermore, we demonstrated that LA increased reactive oxygen species (ROS) production in bacterial cells, activating an oxidative stress response. This response was proved by thioredoxin reductase transcription, and was primarily evident among bacteria cultured in the absence of cysteine. This is the first report of the potential mechanisms involved in bacterial LA transport and stress response in B. breve.
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Boll, Erik Juncker, Bruno I. Cappellozza, and Giuseppe Copani. "PSIII-29 A Novel Direct-Fed Microbial Supports in Vitro Intestinal Integrity Under Inflamed Conditions." Journal of Animal Science 101, Supplement_3 (November 6, 2023): 619–20. http://dx.doi.org/10.1093/jas/skad281.722.
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Abstract Ruminants are often exposed to pathogenic and non-pathogenic challenges during daily handling procedures and management activities. These responses, in turn, may trigger the release of pro-inflammatory compounds that can have negative effects on the host. Based on this rationale, we hypothesized that 1) pro-inflammatory cytokines (TNF-α and IFN-γ) would compromise the in vitro gut barrier integrity, and 2) a novel direct-fed microbial (DFM) formulation would support the gut barrier integrity under inflammatory conditions. Therefore, our objective was to evaluate the ability of a novel DFM mixture to support barrier integrity of intestinal epithelial cell monolayers in the absence or presence of TNF-α and IFN-γ by measuring transepithelial electrical resistance (TEER). Human cancer-derived epithelial intestinal Caco-2 cell monolayers were seeded on transwells for approximately 20 days. A DFM mixture containing Lactobacillus animalis, Propionibacterium freudenreichii, Bacillus licheniformis, and B. subtilis (BOVAMINE DEFEND Plus; Chr. Hansen A/S, Hørsholm, Denmark) at 1.0 × 108 CFU/transwell was then administered to the apical side of the cell monolayers. Then, two hours later a cocktail containing TNF-α / IFN-γ at a 10:1 ratio (100:10 ng/mL, respectively) was added to the basolateral side after which TEER was measured over a 16-h period and used to calculate the area under the curve (AUC). Following the administration of the pro-inflammatory challenge, TEER was decreased, reaching its least concentrations at 5.5 h post-challenge, whereas overall AUC decreased by 21.4% compared with non-challenged control cells. The DFM mixture by itself was able to support the integrity of the intestinal cells by stimulating TEER increase over time and increasing overall AUC vs. non-treated cells (P < 0.01). Moreover, when cells receiving the DFM were challenged with the pro-inflammatory cocktail, TEER concentrations were still above 100% and no decrease was observed over the evaluation period (16 h). Moreover, when compared with non-DFM-treated but challenged cells, AUC was greater for DFM vs. challenged control cells (P < 0.05). In conclusion, these data support our hypothesis that a DFM mixture containing L. animalis, P. freudenreichii, B. licheniformis, and B. subtilis (BOVAMINE DEFEND Plus) supports the gut barrier integrity with or without the pro-inflammatory challenge.
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Mengge, Gao, Jun Kong, Yuqian Sun, Zhidong Wang, Ting-Ting Han, Yu Wang, Xiaosu Zhao, and Xiao Jun Huang. "G-CSF Induces MAIT Cells to Exert Anti-Intestinal Gvhd Effects Dependent on CXCR6 Mediated Chemotaxis." Blood 142, Supplement 1 (November 28, 2023): 2048. http://dx.doi.org/10.1182/blood-2023-181445.
Full textAbstract:
Background: Graft-versus-host disease (GVHD) is a major complication leading to transplantation failure and affecting overall survival after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Granulocyte colony-stimulating factor (G-CSF) can induce T-cell tolerance and altering graft cell components to enhance GVHD prevention in HSCT. MAIT cells are a group of innate immune T cells. It has unique biological properties, including mucosal tissue enrichment, activation of microbial riboflavin derivatives and tissue repair properties, which determine MAIT cells play an important role in mucosal immunity. Previous studies found that a high MAIT cell counts in G-CSF-induced grafts (G-grafts) is associated with a low incidence of gut acute GVHD (aGVHD). However, the effect of G-CSF mobilization on the phenotype, function and its regulatory mechanism in GVHD of MAIT cells has not been elucidated. Methods: MAIT cells in PB samples from four healthy donors before and after G-CSF treatment were isolated for Single-cell RNA sequencing (Figure A). Flow cytometry, In vitro experiment and NOD-SCID-IL-2Rg−/− mice (NSG mice) were performed to observe the phenotypic, functional changes and the dynamic distribution of G-CSF induced donor-derived MAIT cells in recipients. Results: A total of 80709 MAIT cells were divided into 14 clusters. Based on key type-associated marker genes and gene sets, MAIT0 (clusters 5 and 9), MAIT1 (cluster 7), MAIT2 (clusters 4 , 11), Cycling MAIT (clusters 12, 13), Activation (clusters 0, 8), ISG (cluster 10) and MAIT17 (clusters 1,2,3,6) cells were identified (Figure B,C). The subset frequencies and expression signatures of immunosuppression (MAIT2 and Cycling cells from cluster 12) and tissue repair (Activation and MAIT17) were both increased at both transcriptome (Figure D) and protein levels, suggesting that G-CSF enhanced the immune tolerance and tissue repair of MAIT cells. In vitro further confirmed that G-CSF-induced MAIT cells showed a stronger inhibition for T cell proliferation (Figure E). Besides, overexpressed genes related to immune regulation in G-CSF induced MAIT cells were strongly enriched in cluster 12 with high CSF3R (G-CSF receptor) expression (Figure F). The cluster 12 also showed the enrichment of IL-17 and TNF signaling pathway favoring tissue repair function, while downregulation of Graft-versus-host disease pathway upon G-CSF mobilization, indicating that G-CSF-CSF3R interaction is the potential mechanism by which G-CSF mediates the immune regulation of MAIT cells. Based on whether recipients develop gut aGVHD or not after allo-HSCT, the matched donor grafts after G-CSF mobilization were divided into two groups termed as post-G-CSF-no gut aGVHD (n=3) and post-G-CSF-gut aGVHD group (n=1), respectively. MAIT cells in post-G-CSF-no gut aGVHD group overexpressed CSF3R and its related target genes, immunosuppression and tissue repair signatures compared with post-G-CSF-gut aGVHD. Besides, MAIT cells from G-PB of recipients without gut aGVHD had a higher CD114 expression (encoded by CSF3R) compared with gut aGVHD (Figure G). These results suggest that the enhanced immunosuppression and tissue repair function of MAIT cells induced by G-CSF may exert anti-gut aGVHD effects. The NSG mice confirmed MAIT cells in G-PB to tissue chemotaxis especially gut tissues in the recipient. A higher frequency of MAIT cells was detected in gut tissues in the low GVHD score group (GVHD Score＜3) compared with the high GVHD score group on post-transplant day 14 (Figure H), suggesting recruited MAIT cells in gut tissues favor anti-gut aGVHD effect. Moreover, CXCR6 was the most differentially expressed chemotactic receptor gene between post-G-CSF-no gut aGVHD and post-G-CSF-gut aGVHD group (Figure I). At the protein level, the expression of CXCR6 were significantly upregulated upon G-CSF administration (Figure I), while that of CCR6 and CXCR6 was non-significant. These results suggest that CXCR6 is necessary for G-CSF induced MAIT cell recruitment to the gut tissue. Conclusions G-CSF-CSF3R interactions enhance immunosuppression and tissue repair functions of MAIT cells, while CXCR6 recruits these functional MAIT cells from PB to gut tissues to exert anti-gut aGVHD effect. Hence, CSF3R and CXCR6 expression in G-CSF mobilized MAIT cells is crucial to exert anti-gut aGVHD effect, and has the potential to become predictive markers of gut aGVHD.
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Zhang, Hongwei, Sebastian Rausch, and Susanne Hartmann. "High resistance to intestinal nematode infection is associated with a strong bias for TFH cell responses, rapid IgG1 class switch and limited Th2 effector cell expansion." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 99.20. http://dx.doi.org/10.4049/jimmunol.206.supp.99.20.
Full textAbstract:
Abstract Gastrointestinal nematode infections are highly prevalent in nature, lead to considerable morbidity in infected humans and cause high economical loss in animal husbandry. While it is clear that type 2 responses orchestrated by CD4+GATA-3+ Th2 cells are pivotal for the control of GI nematodes, the basis for differential susceptibility of distinct host genetic backgrounds is less well understood. The high resistance of ‘rapid responder’ SJL mice to infections with the small intestinal nematode H. polygyrus is evident in low parasite egg production and the termination of infection within a few weeks. Comparing the SJL line to slow responder C57BL/6 mice, we found that SJL mice generated relatively few Th2 effector cells, many follicular T helper cells and strong antibody responses in spleen and gut draining lymph nodes. These Th2 effector cells of SJL mice expressed high levels of the gut/mucosal homing markers CCR9/a4b7, resulting in the rapid accumulation of Th2 cells in the infected small intestine. Surprisingly, resistance was further associated with exceptionally high proportions of Treg in the spleen of SJL mice at steady state and the vigorous expansion of Treg in mLN after infection. This coincided with a bias for follicular T helper cells expansion in both mLN and spleen and, consequently, more extensive IgG1 class switching by GL7+ germinal center B cells in both organs. Infection-derived B cells transfer provides protection in SJL mice, not in B6 mice. In conclusion, resistance versus susceptibility to primary H. polygyrus infection appears to be less dependent on the overall magnitude of Th2 responses, but rather seems to depend on rapid Th2 effector homing, follicular T helper cells and the rapid instruction of antibody responses.
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Provitera, Livia, Andrea Tomaselli, Genny Raffaeli, Stefania Crippa, Cristina Arribas, Ilaria Amodeo, Silvia Gulden, et al. "Human Bone Marrow-Derived Mesenchymal Stromal Cells Reduce the Severity of Experimental Necrotizing Enterocolitis in a Concentration-Dependent Manner." Cells 12, no. 5 (February 27, 2023): 760. http://dx.doi.org/10.3390/cells12050760.
Full textAbstract:
Necrotizing enterocolitis (NEC) is a devastating gut disease in preterm neonates. In NEC animal models, mesenchymal stromal cells (MSCs) administration has reduced the incidence and severity of NEC. We developed and characterized a novel mouse model of NEC to evaluate the effect of human bone marrow-derived MSCs (hBM-MSCs) in tissue regeneration and epithelial gut repair. NEC was induced in C57BL/6 mouse pups at postnatal days (PND) 3–6 by (A) gavage feeding term infant formula, (B) hypoxia/hypothermia, and (C) lipopolysaccharide. Intraperitoneal injections of PBS or two hBM-MSCs doses (0.5 × 106 or 1 × 106) were given on PND2. At PND 6, we harvested intestine samples from all groups. The NEC group showed an incidence of NEC of 50% compared with controls (p < 0.001). Severity of bowel damage was reduced by hBM-MSCs compared to the PBS-treated NEC group in a concentration-dependent manner, with hBM-MSCs (1 × 106) inducing a NEC incidence reduction of up to 0% (p < 0.001). We showed that hBM-MSCs enhanced intestinal cell survival, preserving intestinal barrier integrity and decreasing mucosal inflammation and apoptosis. In conclusion, we established a novel NEC animal model and demonstrated that hBM-MSCs administration reduced the NEC incidence and severity in a concentration-dependent manner, enhancing intestinal barrier integrity.