Journal articles on the topic 'PAMPs and DAMP'
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1
Chen, Jiann Chu. "The complex of damage-associated molecular pattern and its inducer, pathogen-associated molecular pattern enhance triggering innate immunity in shrimp (VET1P.1128)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 146.16. http://dx.doi.org/10.4049/jimmunol.194.supp.146.16.
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Abstract Peptidoglycan (PG) derived commonly from Gram-positive bacteria, is one of pathogen-associated molecular pattern (PAMP). Incubating hemocytes of shrimp in PG caused degranulation, changes in cell size, reduction in the percentage of cell viability, necrosis of hemocytes, and released intracellular molecules containing damage-associated molecular pattern (DAMP) that is well known in mammals and teleosts. Incubating shrimp hemocytes in PAMP, DAMP or the mixture of PAMPs plus DAMPs all induced significant increases in phenoloxidase (PO) activity and respiratory burst (RB, release of superoxide anion) in vitro. The PO activity and RB induced by the mixture of DAMP-PAMP were much greater than that induced by DAMP alone or PAMP alone. In conclusion, the mixture of DAMP-PAMP cause enhancement in eliciting innate immunity of shrimp. This is the first study to confirm that cell necrosis caused by PAMPs releases intracellular molecules, DAMPs, and the mixture of DAMP-PAMP elicit the innate immunity in an invertebrate.
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Jang, Gun-Young, Ji won Lee, Young Seob Kim, Sung Eun Lee, Hee Dong Han, Kee-Jong Hong, Tae Heung Kang, and Yeong-Min Park. "Interactions between tumor-derived proteins and Toll-like receptors." Experimental & Molecular Medicine 52, no. 12 (December 2020): 1926–35. http://dx.doi.org/10.1038/s12276-020-00540-4.
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AbstractDamage-associated molecular patterns (DAMPs) are danger signals (or alarmins) alerting immune cells through pattern recognition receptors (PRRs) to begin defense activity. Moreover, DAMPs are host biomolecules that can initiate a noninflammatory response to infection, and pathogen-associated molecular pattern (PAMPs) perpetuate the inflammatory response to infection. Many DAMPs are proteins that have defined intracellular functions and are released from dying cells after tissue injury or chemo-/radiotherapy. In the tumor microenvironment, DAMPs can be ligands for Toll-like receptors (TLRs) expressed on immune cells and induce cytokine production and T-cell activation. Moreover, DAMPs released from tumor cells can directly activate tumor-expressed TLRs that induce chemoresistance, migration, invasion, and metastasis. Furthermore, DAMP-induced chronic inflammation in the tumor microenvironment causes an increase in immunosuppressive populations, such as M2 macrophages, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). Therefore, regulation of DAMP proteins can reduce excessive inflammation to create an immunogenic tumor microenvironment. Here, we review tumor-derived DAMP proteins as ligands of TLRs and discuss their association with immune cells, tumors, and the composition of the tumor microenvironment.
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Zanoni, Ivan, and Marco Di Gioia. "Endogenous oxidized phospholipids reprogram cellular metabolism and boost hyperinflammation." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 69.1. http://dx.doi.org/10.4049/jimmunol.204.supp.69.1.
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Abstract Pathogen-associated molecular patterns (PAMPs) have the capacity to couple inflammatory gene expression to changes in macrophage metabolism, both of which influence subsequent inflammatory activities. Similar to their microbial counterparts, several self-encoded damage-associated molecular patterns (DAMPs) induce inflammatory gene expression. However, whether this symmetry in host responses between PAMPs and DAMPs extends to metabolic shifts is unclear. Here we report that the self-encoded oxidized phospholipid oxPAPC alters the metabolism of macrophages exposed to lipopolysaccharide (LPS). While cells activated by LPS rely exclusively on glycolysis, macrophages exposed to oxPAPC also use mitochondrial respiration, feed the Krebs cycle with glutamine and favor the accumulation of oxaloacetate in the cytoplasm: this metabolite potentiates IL-1beta production, resulting in hyperinflammation. Similar metabolic adaptions occur in vivo in hypercholesterolemic mice and human subjects. Drugs that interfere with oxPAPC-driven metabolic changes reduce atherosclerotic plaque formation in mice, thereby underscoring the importance of DAMP-mediated activities in pathophysiological conditions.
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Andersson, Ulf, Kevin J. Tracey, and Huan Yang. "Post-Translational Modification of HMGB1 Disulfide Bonds in Stimulating and Inhibiting Inflammation." Cells 10, no. 12 (November 26, 2021): 3323. http://dx.doi.org/10.3390/cells10123323.
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High mobility group box 1 protein (HMGB1), a highly conserved nuclear DNA-binding protein, is a “damage-associated molecular pattern” molecule (DAMP) implicated in both stimulating and inhibiting innate immunity. As reviewed here, HMGB1 is an oxidation-reduction sensitive DAMP bearing three cysteines, and the post-translational modification of these residues establishes its proinflammatory and anti-inflammatory activities by binding to different extracellular cell surface receptors. The redox-sensitive signaling mechanisms of HMGB1 also occupy an important niche in innate immunity because HMGB1 may carry other DAMPs and pathogen-associated molecular pattern molecules (PAMPs). HMGB1 with DAMP/PAMP cofactors bind to the receptor for advanced glycation end products (RAGE) which internalizes the HMGB1 complexes by endocytosis for incorporation in lysosomal compartments. Intra-lysosomal HMGB1 disrupts lysosomal membranes thereby releasing the HMGB1-transported molecules to stimulate cytosolic sensors that mediate inflammation. This HMGB1-DAMP/PAMP cofactor pathway slowed the development of HMGB1-binding antagonists for diagnostic or therapeutic use. However, recent discoveries that HMGB1 released from neurons mediates inflammation via the TLR4 receptor system, and that cancer cells express fully oxidized HMGB1 as an immunosuppressive mechanism, offer new paths to targeting HMGB1 for inflammation, pain, and cancer.
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Shamilov, Rambon, Tyler W. Ackley, and Brian J. Aneskievich. "Enhanced Wound Healing- and Inflammasome-Associated Gene Expression in TNFAIP3-Interacting Protein 1- (TNIP1-) Deficient HaCaT Keratinocytes Parallels Reduced Reepithelialization." Mediators of Inflammation 2020 (April 21, 2020): 1–14. http://dx.doi.org/10.1155/2020/5919150.
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TNIP1 protein is a widely expressed, cytoplasmic inhibitor of inflammatory signaling initiated by membrane receptors such as TLRs which recognize pathogen-associated and damage-associated molecular patterns (PAMPs and DAMPs). Keratinocyte TNIP1 deficiency sensitizes cells to PAMPs and DAMPs promoting hyperresponsive expression and secretion of cytokine markers (e.g., IL-8 and IL-6) relevant to cases of chronic inflammation, like psoriasis, where TNIP1 deficiency has been reported. Here, we examined the impact of TNIP1 deficiency on gene expression and cellular responses (migration and viability) relevant to acute inflammation as typically occurs in wound healing. Using siRNA-mediated TNIP1 expression knockdown in cultured HaCaT keratinocytes, we investigated TNIP1 deficiency effects on signaling downstream of TLR3 agonism with low-concentration poly (I:C), a representative PAMP/DAMP. The combination of TNIP1 knockdown and PAMP/DAMP signaling disrupted expression of specific keratinocyte differentiation markers (e.g., transglutaminase 1 and involucrin). These same conditions promoted synergistically increased expression of wound-associated markers (e.g., S100A8, TGFβ, and CCN2) suggesting potential benefit of increased inflammatory response from reduced TNIP1 protein. Unexpectedly, poly (I:C) challenge of TNIP1-deficient cells restricted reepithelialization and reduced cell viability. In these cells, there was not only increased expression for genes associated with inflammasome assembly (e.g., ASC, procaspase 1) but also for A20, a TNIP1 partner protein that represses cell-death signaling. Despite this possibly compensatory increase in A20 mRNA, there was a decrease in phospho-A20 protein, the form necessary for quenching inflammation. Hyperresponsiveness to poly (I:C) in TNIP1-deficient keratinocytes was in part mediated through p38 and JNK pathways. Taken together, we conclude that TNIP1 deficiency promotes enhanced expression of factors associated with promoting wound healing. However, the coupled, increased potential priming of the inflammasome and reduced compensatory activity of A20 has a net negative effect on overall cell recovery potential manifested by poor reepithelialization and viability. These findings suggest a previously unrecognized role for TNIP1 protein in limiting inflammation during successful progression through early wound healing stages.
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Negishi, Hideo, Nobuyasu Endo, Yuki Nakajima, Tatsuaki Nishiyama, Yuichiro Tabunoki, Junko Nishio, Ryuji Koshiba, et al. "Identification of U11snRNA as an endogenous agonist of TLR7-mediated immune pathogenesis." Proceedings of the National Academy of Sciences 116, no. 47 (November 6, 2019): 23653–61. http://dx.doi.org/10.1073/pnas.1915326116.
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The activation of innate immune receptors by pathogen-associated molecular patterns (PAMPs) is central to host defense against infections. On the other hand, these receptors are also activated by immunogenic damage-associated molecular patterns (DAMPs), typically released from dying cells, and the activation can evoke chronic inflammatory or autoimmune disorders. One of the best known receptors involved in the immune pathogenesis is Toll-like receptor 7 (TLR7), which recognizes RNA with single-stranded structure. However, the causative DAMP RNA(s) in the pathogenesis has yet to be identified. Here, we first developed a chemical compound, termed KN69, that suppresses autoimmunity in several established mouse models. A subsequent search for KN69-binding partners led to the identification of U11 small nuclear RNA (U11snRNA) as a candidate DAMP RNA involved in TLR7-induced autoimmunity. We then showed that U11snRNA robustly activated the TLR7 pathway in vitro and induced arthritis disease in vivo. We also found a correlation between high serum level of U11snRNA and autoimmune diseases in human subjects and established mouse models. Finally, by revealing the structural basis for U11snRNA’s ability to activate TLR7, we developed more potent TLR7 agonists and TLR7 antagonists, which may offer new therapeutic approaches for autoimmunity or other immune-driven diseases. Thus, our study has revealed a hitherto unknown immune function of U11snRNA, providing insight into TLR7-mediated autoimmunity and its potential for further therapeutic applications.
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Hirai, K., H. Furusho, N. Kawashima, S. Xu, M. C. de Beer, R. Battaglino, T. Van Dyke, P. Stashenko, and H. Sasaki. "Serum Amyloid A Contributes to Chronic Apical Periodontitis via TLR2 and TLR4." Journal of Dental Research 98, no. 1 (September 6, 2018): 117–25. http://dx.doi.org/10.1177/0022034518796456.
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In the current concept of bacterial infections, pathogen-associated molecular patterns (PAMPs) derived from pathogens and damage-associated molecular patterns (DAMPs) released from damaged/necrotic host cells are crucial factors in induction of innate immune responses. However, the implication of DAMPs in apical and marginal periodontitis is unknown. Serum amyloid A (SAA) is a DAMP that is involved in the development of various chronic inflammatory diseases, such as rheumatoid arthritis. In the present study, we tested whether SAA is involved in the pathogenesis of periapical lesions, using human periapical surgical specimens and mice deficient in SAA and Toll-like receptors (TLR). SAA1/2 was locally expressed in human periapical lesions at the mRNA and protein levels. The level of SAA protein appeared to be positively associated with the inflammatory status of the lesions. In the development of mouse periapical inflammation, SAA1.1/2.1 was elevated locally and systemically in wild-type (WT) mice. Although SAA1.1/2.1 double-knockout and SAA3 knockout mice had redundant attenuation of the extent of periapical lesions, these animals showed strikingly improved inflammatory cell infiltration versus WT. Recombinant human SAA1 (rhSAA1) directly induced chemotaxis of WT neutrophils in a dose-dependent manner in vitro. In addition, rhSAA1 stimulation significantly prolonged the survival of WT neutrophils as compared with nonstimulated neutrophils. Furthermore, rhSAA1 activated the NF-κB pathway and subsequent IL-1α production in macrophages in a dose-dependent manner. However, TLR2/TLR4 double deficiency substantially diminished these SAA-mediated proinflammatory responses. Taken together, the SAA-TLR axis plays an important role in the chronicity of periapical inflammation via induction of inflammatory cell infiltration and prolonged cell survival. The interactions of PAMPs and DAMPs require further investigation in dental/oral inflammation.
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Scalfone, Lisa K., Hendrik J. Nel, Lucille F. Gagliardo, Jody L. Cameron, Shaikha Al-Shokri, Cynthia A. Leifer, Padraic G. Fallon, and Judith A. Appleton. "Participation of MyD88 and Interleukin-33 as Innate Drivers of Th2 Immunity to Trichinella spiralis." Infection and Immunity 81, no. 4 (February 12, 2013): 1354–63. http://dx.doi.org/10.1128/iai.01307-12.
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ABSTRACTTrichinella spiralisis a highly destructive parasitic nematode that invades and destroys intestinal epithelial cells, injures many different tissues during its migratory phase, and occupies and transforms myotubes during the final phase of its life cycle. We set out to investigate the role in immunity of innate receptors for potential pathogen- or danger-associated molecular patterns (PAMPs or DAMPs). Focusing on the MyD88-dependent receptors, which include Toll-like receptors (TLRs) and interleukin-1 (IL-1) family members, we found that MyD88-deficient mice expelled worms normally, while TLR2/4-deficient mice showed accelerated worm expulsion, suggesting that MyD88 was active in signaling pathways for more than one receptor during intestinal immunity. A direct role for PAMPs in TLR activation was not supported in a transactivation assay involving a panel of murine and human TLRs. Mice deficient in the IL-1 family receptor for the DAMP, IL-33 (called ST2), displayed reduced intestinal Th2 responses and impaired mast cell activation. IL-33 was constitutively expressed in intestinal epithelial cells, where it became concentrated in nuclei within 2 days of infection. Nuclear localization was an innate response to infection that occurred in intestinal regions where worms were actively migrating. Th2 responses were also compromised in the lymph nodes draining the skeletal muscles of ST2-deficient mice, and this correlated with increased larval burdens in muscle. Our results support a mechanism in which the immune system recognizes and responds to tissue injury in a way that promotes Th2 responses.
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Dwyer, Gaelen K., Lisa Mathews, Anna Lucas, Bruce R. Blazar, Amanda Poholek, Warren Shlomchik, and Heth Roderick Turnquist. "IL-33 upregulated in fibroblastic reticular cells after recipient conditioning acts as a novel costimulatory signal in the generation of alloreactive Type 1 T helper cells." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 175.08. http://dx.doi.org/10.4049/jimmunol.208.supp.175.08.
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Abstract In allogeneic hematopoietic stem cell transplantation (alloHCT), recipient conditioning releases Pathogen- and Damage-Associated Molecular Patterns (PAMPs and DAMPs) that generate pro-inflammatory antigen-presenting cells (APC) that secrete IL-12 to initiate donor Type 1 T helper (Th1) responses causing graft-vs-host-disease (GVHD). Yet, other mechanisms exist to initiate alloimmune responses, as recipients with disrupted APC PAMP/DAMP signaling or lacking IL-12 develop GVHD. We used IL-33 receptor, ST2, deficient B6 mice as T cell donors into BALB/c recipients to test the hypothesis that the DAMP IL-33 bypasses APC and acts directly on donor CD4+ T cells to mediate early alloreactive T cells activation and differentiation. In our model, we transferred equal ratios of B6 Cd4-Cre x St2fl/fl (ST2ko) and Cd4-Cre (ST2wt) T cells into irradiated BALB/c recipients with and without IL-12 blockade. Donor T cells in the secondary lymphoid organs (SLOs) were characterized at days 1–3, 5, and 7 post alloHCT. We established that IL-33 DAMP functions involve the direct stimulation of donor CD4+ T cells, which promoted IL-12-independent Type 1 T helper cell (Th1) differentiation and expansion. We demonstrated that IL-33 is induced by recipient irradiation in PDPN+CD31− fibroblastic reticular cells (FRC) of the SLOs as early as 1 day post-radiation to increase alloreactive CD4+ T cell numbers. Mechanistically, IL-33 amplified CD4+ T cell TCR signaling in response to alloantigen to enhance Th1 cell activation and differentiation, while inhibiting regulatory molecule (i. e. IL-10 and Foxp3) expression. Thus, IL-33 is an unappreciated costimulatory signal in Th1 generation and a promising early target to prevent acute GVHD after alloHCT. Supported by NIH F30AI147437 and T32 CA082084 (GKD), NIH R01HL122489, R01AR073527, R56AI13927 (HRT)
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Idrus, Hasta Handayani, Mochammad Hatta, Vivien Novarina Kasim, Ami Febriza Achmad, Andi Sitti Fahirah Arsal, Veny hadju, and Suryani As'ad. "Molecular Impact on High Motility Group Box-1 (HMGB-1) in Pamps and Damp." Indian Journal of Public Health Research & Development 10, no. 8 (2019): 1109. http://dx.doi.org/10.5958/0976-5506.2019.02045.x.
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Yang, Huan, Haichao Wang, Zhongliang Ju, Ahmed A. Ragab, Peter Lundbäck, Wei Long, Sergio I. Valdes-Ferrer, et al. "MD-2 is required for disulfide HMGB1–dependent TLR4 signaling." Journal of Experimental Medicine 212, no. 1 (January 5, 2015): 5–14. http://dx.doi.org/10.1084/jem.20141318.
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Innate immune receptors for pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) orchestrate inflammatory responses to infection and injury. Secreted by activated immune cells or passively released by damaged cells, HMGB1 is subjected to redox modification that distinctly influences its extracellular functions. Previously, it was unknown how the TLR4 signalosome distinguished between HMGB1 isoforms. Here we demonstrate that the extracellular TLR4 adaptor, myeloid differentiation factor 2 (MD-2), binds specifically to the cytokine-inducing disulfide isoform of HMGB1, to the exclusion of other isoforms. Using MD-2–deficient mice, as well as MD-2 silencing in macrophages, we show a requirement for HMGB1-dependent TLR4 signaling. By screening HMGB1 peptide libraries, we identified a tetramer (FSSE, designated P5779) as a specific MD-2 antagonist preventing MD-2–HMGB1 interaction and TLR4 signaling. P5779 does not interfere with lipopolysaccharide-induced cytokine/chemokine production, thus preserving PAMP-mediated TLR4–MD-2 responses. Furthermore, P5779 can protect mice against hepatic ischemia/reperfusion injury, chemical toxicity, and sepsis. These findings reveal a novel mechanism by which innate systems selectively recognize specific HMGB1 isoforms. The results may direct toward strategies aimed at attenuating DAMP-mediated inflammation while preserving antimicrobial immune responsiveness.
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Artemyeva, O. V., and L. V. Gankovskaya. "Inflammaging as the basis of age-associated diseases." Medical Immunology (Russia) 22, no. 3 (May 21, 2020): 419–32. http://dx.doi.org/10.15789/1563-0625-iat-1938.
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Aging is one of the most complex biological phenomena that affects all human physiological systems, including the immune system. Immunosenescence is understood as structural and functional changes in both adaptive and innate immunity systems. The so-called inflammaging is among manifestations of immune aging. It is an age-related increase in inflammatory mediators and development of an inflammatory phenotype. An important role in development of inflammaging is assigned to chronic stimulation of immune system by exogenous and endogenous danger signals (pathogen-associated molecular pattern, PAMP and damage-associated molecular pattern, DAMP), which include viruses, microbiota of the gastrointestinal tract, free radicals, etc. PAMP and DAMP are recognized by the innate immunity system cells through the pattern recognition receptors (PRR), e.g., Toll-like receptors (TLR), RIG-I-like receptors (RLR), NODlike receptors (NLR), lectin receptors. Stimulation of PRR leads to activation of intracellular signaling and increased expression of pro-inflammatory factors. PAMPs are the most powerful activators of PRR and inflammation triggers; DAMPs can activate the same receptors and signaling pathways, causing the development of a sterile inflammatory response. The NF-kB signaling pathway is considered as a key signaling pathway for inflammaging. NLR stimulation also leads to formation of inflammasome. Its function is to transform the pro-inflammatory cytokines to a biologically active form, which is an important for the formation of a pro-inflammatory phenotype and development of inflammaging. This process is considered an important risk factor for morbidity and mortality among older people. Chronic inflammation underlies pathogenesis of many age-related diseases, such as osteoporosis, atherosclerosis, Alzheimer’s disease, Parkinson’s disease, type 2 diabetes. Various chronic diseases associated with age are directly related to PAMP and DAMP-induced TLR or NLRP3-mediated inflammatory response. Hence, these ligands and their receptors can be suggested as biomarkers and interventional targets for age-related disorders. Despite numerous studies in age-associated pathology, there are only few works on the contribution of innate immunity in healthy aging. It remains unclear whether the inflammatory phenotype is a manifestation of healthy aging, or it is associated with development of age-related pathology. Further study of the mechanisms of inflammatory aging will reveal biomarkers of healthy aging and potential targets for the treatment of age-associated diseases.
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Germoglio, Marcello, Adele Adamo, Guido Incerti, Fabrizio Cartenì, Silvia Gigliotti, Aurora Storlazzi, and Stefano Mazzoleni. "Self-DNA Exposure Induces Developmental Defects and Germline DNA Damage Response in Caenorhabditis elegans." Biology 11, no. 2 (February 8, 2022): 262. http://dx.doi.org/10.3390/biology11020262.
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All organisms, from bacteria to mammals, sense and respond to foreign nucleic acids to fight infections in order to survive and preserve genome integrity across generations. The innate immune system is an evolutionarily conserved defence strategy. Complex organisms have developed various cellular processes to respond to and recognise not only infections, i.e., pathogen-associated molecular patterns (PAMPs), but also to sense injury and tissue dysfunctions, i.e., damage-associated molecular patterns (DAMPs). Mis-localized self-DNA can be sensed as DAMP by specific DNA-sensing pathways, and self-DNA chronic exposure can be detrimental to the organisms. Here, we investigate the effects of dietary delivered self-DNA in the nematode Caenorhabditis elegans. The hermaphrodite worms were fed on Escherichia coli genomic libraries: a C. elegans library (self) and a legume (Medicago truncatula) library (non-self). We show that the self-library diet affects embryogenesis, larval development and gametogenesis. DNA damage and activation of p53/CEP-1-dependent apoptosis occur in gonadal germ cells. Studies of self-DNA exposure in this model organism were not pursued up to now. The genetic tractability of C. elegans will help to identify the basic molecular pathways involved in such mechanisms. The specificity of the adverse effects associated with a self-DNA enriched diet suggests applications in biological pest control approaches.
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Semenova, I. B. "ROLE OF PURINERGIC RECEPTORS IN IMMUNE RESPONSE." Journal of microbiology, epidemiology and immunobiology, no. 2 (April 28, 2016): 107–19. http://dx.doi.org/10.36233/0372-9311-2016-2-107-119.
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Purine receptors are located on immune and somatic cells of animal and human organisms. Summation of signals from purine and TOLL-like receptors takes place on the level of inflammasome formation and results in summation of the first and second signals of innate immunity. The first signal - from PAMPs (pathogen associated molecular patterns), the second - from DAMPs (danger associated molecular patterns). Adenosine triphosphate (ATP) is the most studied DAMP. ATP connects with purine receptors, which include P2 (P2X7 receptors are the best described), that results in opening of channels of these receptors and transit of ATP into the cell. In parallel exit of K+ from cells and entrance of Ca2+ and Na+ into the cells is observed, that is associated with activation of the immune competent cell. Damaged cells dying via necrosis or apoptosis are the source of extracellular ATP, as well as activated immunocytes. Signals from P2 and TOLL-like receptors are summarized in effectors of immune response, and activation of P2 receptors in lymphocytes makes a contribution into activation of cells, mediated by T-cell receptor. Negative side of purine receptor activation is a stimulating effect on proliferation and metastasis of malignant cells. The practical output of knowledge on functioning of purine receptors for clinical immunology is the application of agonists and antagonists of purine receptors, as well as explanation of effect of immune modulators from the position of launch of K+/Na+-pump, resulting in prolonged activation of immune competent cells.
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Mertowski, Sebastian, Ewelina Grywalska, Jarosław Ludian, Agnieszka Grafka, Barbara Pęksa, Jacek Roliński, and Wojciech Załuska. "The significance of Toll-like receptors in selected nephropathies." Diagnostyka Laboratoryjna 55, no. 2 (April 5, 2019): 107–12. http://dx.doi.org/10.5604/01.3001.0013.7445.
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The diseases associated with kidney damage are an increasingly common problem in modern society and complications of chronic renal failure can result in death. Research conducted by many scientific centers, both Polish and foreign, concern the search for possible factors involved in the pathogenesis of glomerulonephritis. One of the possible causes of nephropathy may include the dysfunction of Toll-like receptors (TLRs), which constitute a “bridge” between innate and acquired response. TLRs are involved in receiving signals related to pathogen associated molecular patterns (PAMPs) as well as receiving information related to the danger associated molecular patterns (DAMP). The stimulation of these receptors activates a cascade of reactions in the course of which various mediators, including pro-inflammatory mediators, are produced. The resulting long-lasting inflammation that develops within the glomerulus may cause kidney damage. In both nephropathies caused by excessive production of antibodies in the IgA class, as well as nephropathy induced by diabetes or lupus, the expression of individual TLRs may indicate an inducer of an inflammatory reaction cascade that leads to kidney damage. This article focuses on literature reports that present current views on the role of TLRs in the pathogenesis of the most common nephropathies.
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Wang, Yifei, and Robert J. Binder. "CD91-Dependent Release of IL-1β by GP96 Involves the Activation of the Inflammasome Complex." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 151.23. http://dx.doi.org/10.4049/jimmunol.198.supp.151.23.
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Abstract The immunogenic heat shock protein, gp96, binds to CD91 to elite an immune response, characterized by cross-presentation of chaperoned peptides and release of cytokines, including IL-1β. IL-1β is pro-inflammatory cytokine, which is secreted by immune cells upon sensing pathogen associated molecular pattern (PAMP) or damage associated molecular pattern (DAMP). IL-1β is synthesized as a precursor protein, and requires cleavage by Caspase-1 to the matured IL-1β which is released from the cells. Caspase-1 activation requires the inflammasome protein complex. For Inflammasome activation, signal 1 induces pro-inflammatory gene transcription, and signal 2 activates Inflammasome. We have previously shown that gp96 induces NFκB activation and IL-1β secretion via CD91.1 Here we examined the utilization of the inflammasome for IL-1β in this setting. We report that gp96 is able to work as signal 1 to prime production of pro-IL-1β in APCs and in a dose-dependent manner. The kinetics of priming pro-IL-1β differ between gp96 and other PAMPs such as LPS. We will explore the dependence of IL-1β release on the inflammasome.
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Pandya, Unnati, Chinaza Egbuta, Trefa Abdullah Norman, Chih-Yuan Chiang, Valerie Wiersma, Rekha Panchal, Edwin Bremer, Paul Eggleton, and Leslie Gold. "The Biophysical Interaction of the Danger-Associated Molecular Pattern (DAMP) Calreticulin with the Pattern-Associated Molecular Pattern (PAMP) Lipopolysaccharide." International Journal of Molecular Sciences 20, no. 2 (January 18, 2019): 408. http://dx.doi.org/10.3390/ijms20020408.
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The endoplasmic reticulum (ER) chaperone protein, calreticulin (CRT), is essential for proper glycoprotein folding and maintaining cellular calcium homeostasis. During ER stress, CRT is overexpressed as part of the unfolded protein response (UPR). In addition, CRT can be released as a damage-associated molecular pattern (DAMP) molecule that may interact with pathogen-associated molecular patterns (PAMPs) during the innate immune response. One such PAMP is lipopolysaccharide (LPS), a component of the gram-negative bacterial cell wall. In this report, we show that recombinant and native human placental CRT strongly interacts with LPS in solution, solid phase, and the surface of gram-negative and gram-positive bacteria. Furthermore, LPS induces oilgomerization of CRT with a disappearance of the monomeric form. The application of recombinant CRT (rCRT) to size exclusion and anion exchange chromatography shows an atypical heterogeneous elution profile, indicating that LPS affects the conformation and ionic charge of CRT. Interestingly, LPS bound to CRT is detected in sera of bronchiectasis patients with chronic bacterial infections. By ELISA, rCRT dose-dependently bound to solid phase LPS via the N- and C-domain globular head region of CRT and the C-domain alone. The specific interaction of CRT with LPS may be important in PAMP innate immunity.
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Trova, Sandro, Matthew Fenton, Bhavini Chauhan, Avani Puri, Santosh Lomada, Alexandra Adams, Thomas Wieland, et al. "Human and Pathogen Derived Ndpks Act As Novel Damps and PAMPs to Drive Leukemia Cell Survival and Progression through Signaling Via the TLR4-Mediated Alternative NLRP3 Inflammasome Pathway." Blood 134, Supplement_1 (November 13, 2019): 2684. http://dx.doi.org/10.1182/blood-2019-131236.
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Elevated plasma levels of the nucleoside diphosphate kinase (NDPK) NM23-H1 are associated with poorer prognosis in acute myeloid leukemia (AML). We previously demonstrated that leukemic blasts release NM23-H1, which binds to more differentiated myeloid cells inducing their secretion of inflammatory cytokines, including IL-1β, that promote survival and proliferation of leukemic blasts1. Both AML and myelodysplastic syndrome (MDS) patients are prone to infections due to impaired hematopoiesis that is worsened by treatment. NDPKs are highly evolutionarily conserved raising the possibility that bacterial/fungal NDPKs could mediate the same survival effect on malignant AML/MDS blasts and exacerbate disease progression. To test this, we generated recombinant NDPKs (rNDPKs) from bacteria and fungi associated with common infections in these patients (E. coli, S. aureus, S. pneumoniae, K. pneumoniae, C. albicans). Cytokine production and survival responses of primary AMLs to these proteins were indistinguishable from their response to rNM23-H1. This activity was independent of NDPK enzyme activity since mutant rNM23-H1 and bacterial and fungal rNDPKs with impaired oligomerization, kinase or exonuclease activity elicited the same cytokine and survival response. Toll like receptors (TLRs) are the major family of human DAMP/PAMP receptors and IL-1β secretion is closely associated with TLR-4 mediated activation of the NLRP3 inflammasome in monocytes. We therefore postulated that NM23-H1 and pathogen derived NDPKs act as novel damage- and pathogen- associated molecular pattern (DAMP, PAMP) molecules. We confirmed that fluorescently labelled rNM23-H1 and S. pneumoniae rNDPK bound selectively to monocytes in peripheral blood. Using in vitro generated monocytes (vitamin D3 differentiated THP-1 cells) we demonstrated that both wild type and mutant rNM23-H1 and bacterial/fungal rNDPKs induced activation of caspase-1 and cleavage of pro-IL-1β into its active form. Secretion of IL-1β was inhibited by antagonists/inhibitors of TLR4, NLRP3 and caspase-1 indicating the involvement of the TLR4-NLRP3 inflammasome axis is mediating the NDPK response. Unlike the canonical NLRP3-inflammasome pathway that leads to monocyte cell death by pyroptosis, rNM23-H1 and rNDPKs did not lead to cell death indicating that rNDPKs are responsible for the activation of the alternative inflammasome. In our earlier studies, and those of others, we demonstrated that not all AML primary samples responsed to NM23-H1 in vitro. We have observed that non responders to NM23-H1 also do not respond to pathogen derived rNDPKs. In contrast, we have observed uniform responses in terms of cytokine release in all normal peripheral blood. We hence hypothesized that the non-rNDPK-responding AML samples may reflect the absence of monocytes in culture. To test this, we generated conditioned media using normal donor leukocytes, in presence or absence of a TLR-4 antagonist to inhibit the IL-1β production. The conditioned media was then used to culture primary AML samples, in parallel with rNDPK in unconditioned media. All the samples analyzed showed increased survival in rNDPK conditioned media even whilst some did not respond to rNDPK in unconditioned media. In summary, our data demonstrate for the first time that NM23-H1 and bacterial/fungal NDPKs are novel DAMPs/PAMPS that signal via TLR4 in monocytes. We further demonstrate that this interaction results in activation of the alternative NLRP3 inflammasome and subsequent cleavage and secretion of IL-1β without death by pyroptosis. Our data showing that bacterial/fungal NDPKs can promote survival of AML blasts indicates that rather than just being a consequence of AML associated immunosuppression, infections may drive the progression and AML. These findings have important implications in the clinical management of AML and its precursor myelodysplastic syndromes (MDS). Lilly AJ, et al.Cancer Res. 2011;71(3):1177-86.Gaidt MM, et al. Immunity. 2016;44(4):833-46 Disclosures Drayson: Abingdon Health: Consultancy, Equity Ownership.
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Iurescia, Sandra, Daniela Fioretti, and Monica Rinaldi. "The Innate Immune Signalling Pathways: Turning RIG-I Sensor Activation against Cancer." Cancers 12, no. 11 (October 27, 2020): 3158. http://dx.doi.org/10.3390/cancers12113158.
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Over the last 15 years, the ability to harness a patient’s own immune system has led to significant progress in cancer therapy. For instance, immunotherapeutic strategies, including checkpoint inhibitors or adoptive cell therapy using chimeric antigen receptor T-cell (CAR-T), are specifically aimed at enhancing adaptive anti-tumour immunity. Several research groups demonstrated that adaptive anti-tumour immunity is highly sustained by innate immune responses. Host innate immunity provides the first line of defence and mediates recognition of danger signals through pattern recognition receptors (PRRs), such as cytosolic sensors of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular pattern (DAMP) signals. The retinoic acid-inducible gene I (RIG-I) is a cytosolic RNA helicase, which detects viral double-strand RNA and, once activated, triggers signalling pathways, converging on the production of type I interferons, proinflammatory cytokines, and programmed cell death. Approaches aimed at activating RIG-I within cancers are being explored as novel therapeutic treatments to generate an inflammatory tumour microenvironment and to facilitate cytotoxic T-cell cross-priming and infiltration. Here, we provide an overview of studies regarding the role of RIG-I signalling in the tumour microenvironment, and the most recent preclinical studies that employ RIG-I agonists. Lastly, we present a selection of clinical trials designed to prove the antitumour role of RIG I and that may result in improved therapeutic outcomes for cancer patients.
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Merkushova, E. D., E. M. Khasanova, and L. V. Gankovskaya. "Mechanisms of innate immunity in pathogenesis of psoriasis: approaches to targeted therapy." Medical Immunology (Russia) 22, no. 3 (May 21, 2020): 449–58. http://dx.doi.org/10.15789/1563-0625-moi-1949.
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Psoriasis is a chronic auto-inflammatory, genetically determined dermatosis, being multifactorial by origin, characterized by hyperproliferation of epidermis, affected keratinocyte differentiation and inflammatory reaction in dermis. The disease is characterized by a tendency to spread over the area of lesion, and involvement of articular tissue in the pathological process, which significantly affects the living standards of patients and causes their disability. There are many provoking factors that contribute to occurrence of psoriasis, or progression of existing psoriatic process in individuals with a genetic predisposition. These factors include adverse climatic conditions, skin trauma, exposure to ultraviolet light, burns, infections, etc.This review describes the role of innate immunity in pathogenesis of psoriasis, and describes in detail the mechanisms involved into induction of inflammation of PAMPs and DAMPs. In psoriasis, positively charged catelicidin is considered one of the most important DAMPs, which can form a complex with negatively charged cell polyanions-LL-37/auto-RNA and LL-37/auto-DNA. The interaction of PAMP/DAMP ligands with specific PRR receptors leads to signal activation of effector components of immune system, i.e., assembly of inflammasome complex, caspase activation, synthesis of inflammatory cytokines and processing of their immature forms. The review focuses on the role of TLRs under the conditions of physiological norm, which recognize danger signals and provide protection from pathogens and their timely elimination, and in development of pathological process. Activation of TLRs induces the production of pro-inflammatory cytokines, interferons and antimicrobial peptides, chemokines that support the development of psoriatic inflammation.In addition to TLRs, the mechanisms of involvement of inflammasomes in the development of psoriasis, which provides processing of mature forms of IL-1β and IL-18, are described in detail. Mature forms of these cytokines mediate the development of inflammation in psoriatic focus. In addition, processing of these cytokines by caspases using the positive feedback mechanism provides an additional signal to activate transcriptional activity of their genes and contributes to perpetuated inflammation.The review presents data confirming participation of inflammasomes in the pathogenesis of psoriasis. Much attention is paid to description of pharmacological inhibitors of inflammasomes, which in the future may be the drugs of choice for treatment of inflammatory diseases. The study of molecular mechanisms of the innate immune system will reveal new approaches to prognosis and development of targeted therapy for psoriasis.
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Dosch, Michel Ernest, Tamara Salamanca, Djulia Djonova, Adrian Keogh, Deborah Stroka, Daniel Candinas, and Guido Beldi. "Could Connexin 43 dependent ATP release represent a new therapeutic target for sepsis?" Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 125.32. http://dx.doi.org/10.4049/jimmunol.198.supp.125.32.
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Abstract During sepsis, ATP is released into the extracellular space where it modulates immune response via specific receptors and ectonucleotidases present on various immune cells. ATP can be released by hemichannel Connexin 43 (Cx43). Here, we examine the importance of Cx43 mediated ATP release in macrophages and the role of this pathway in modulating innate immune responses in the context of sepsis. For murine sepsis model, caecal ligation and puncture (CLP) was used. Mice were treated with Gap27, a Cx43 inhibitor. Liver, lung, spleen, bone marrow, peritoneal fluid and blood cells expressing Cx43 were characterized (IHC, FACS). Macrophages were isolated from peritoneum and liver of wild-type mice and stimulated with PAMPs. ATP was quantified using luciferin-luciferase assay. Cytokine levels (ELISA), gene expression (qPCR) and protein expression (immunoblot) were assessed. Blocking of Cx43 during CLP prolonged survival up to 48 hours in comparison with 24 hours for controls. In addition, it decreased systemic levels of inflammatory cytokines (TNFa, IL1b and IL6) and chemokines (CCL2) and lowered bacterial load (CFU/ml) in the blood and peritoneal fluid. Cx43 was not constitutively expressed in the liver, but was induced following CLP. Cells expressing Cx43 in septic livers were identified as infiltrating M1 macrophages and neutrophils. Ex vivo, Cx43 expression was upregulated in primary macrophages upon stimulation with LPS. Macrophages were actively releasing ATP in response to TLR 4 and 2 agonists, and Cx43 inhibition reduced extracellular ATP levels. We observed improved survival to sepsis by blocking Cx43. By mediating release of ATP, and potentially other DAMP, Cx43 might overactivate macrophages and exacerbate the immune response.
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Lee, Chih-Chun, Chun-Yu Tung, Ching Ching Wu, and Tsang Long Lin. "AVIAN INNATE IMMUNITY WITH AN EMPHASIS ON CHICKEN MELANOMA DIFFERENTIATION-ASSOCIATED GENE 5 (MDA5)." Taiwan Veterinary Journal 45, no. 03 (August 30, 2019): 43–55. http://dx.doi.org/10.1142/s1682648519300016.
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Avian species have immune system to fight invading pathogens. The immune system comprises innate and adaptive immunity. Innate immunity relies on pattern recognition receptors to sense particular molecules present in pathogens, i.e. pathogen-associated molecular patterns (PAMPs), or danger signals in the environment, i.e. danger-associated molecular patterns (DAMPs). Cytoplasmic retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) and nucleotide-binding oligomerization domain-like receptors (NLRs) are the sensors recognizing cytoplasmic PAMP and/or DAMP. Among common avian species, chickens do not have RIG-I whereas ducks and finches do. Therefore, the other RLR member, melanoma differentiation-associated gene 5 (MDA5), is believed to play an important role to recognize intracellular pathogens in chickens. Chicken MDA5 has been identified and its function determined. Chicken MDA5 maintains the same domain architecture compared with MDA5 analogs in other animal species. The expression of chicken MDA5 was upregulated when a synthetic double-stranded RNA (dsRNA), polyriboinosinic:polyribocytidylic acids (poly(I:C)), was transfected into chicken cells, whereas that did not change when cells were incubated with poly(I:C). The enhanced expression of chicken MDA5 in chicken cells upregulated the expression of chicken interferon-[Formula: see text] (IFN-[Formula: see text]). The infection of dsRNA infectious bursal disease virus (IBDV) in non-immune cells triggered the activation of chicken MDA5 signaling pathway, leading to the production of IFN-[Formula: see text] and subsequent response of IFN-stimulated genes. Furthermore, in immune cells like macrophages, chicken MDA5 participated in sensing the infection of IBDV by activating downstream antiviral genes and molecules and modulating adaptive immunity.On the contrary, one of cytoplasmic NLR member, NLR family pyrin domain containing 3 (NLRP3), was cloned and functionally characterized in chicken cells. Chicken NLRP3 conserved the same domain architecture compared with NLRP3 analogs in other animal species. Chicken NLRP3 was highly expressed in kidney, bursa of Fabricius and spleen. The production of mature chicken interleukin 1 [Formula: see text] (IL-1[Formula: see text] in chicken macrophages was stimulated by lipopolysaccharide (LPS) treatment followed by short ATP exposure.In summary, chicken MDA5 was a cytoplasmic dsRNA sensor that mediated the production of type I IFN upon ligand engagement, whereas NLRP3 sensed danger signals, such as ATP, in the cytoplasm and cleaved pro-IL-1[Formula: see text] to produce mature IL-1[Formula: see text]. Chicken MDA5 was not only involved in the activation of innate immune responses in non-immune and immune cells, but it also participated in modulating adaptive immunity in immune cells. Chicken NLRP3 participated in the production of mature chicken IL-1[Formula: see text] upon ligand engagement.
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Toubai, Tomomi, Corinne Rossi, Katherine Oravecz-Wilson, Nathan Mathewson, Cynthia Zajac, Chen Liu, Stuart Brabbs, et al. "Donor T Cells Intrinsic Responses to Damps Regulated By Siglec-G-CD24 Axis Mitigate Gvhd but Maintain GVL in Experimental BMT Model." Blood 126, no. 23 (December 3, 2015): 229. http://dx.doi.org/10.1182/blood.v126.23.229.229.
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Abstract Innate immune receptors like pattern recognition receptors (PRRs) including toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD) like-receptors (NLR) on immune cells play an important role in initiating inflammatory responses to damage- and pathogen- associated molecular patterns (DAMPs and PAMPs) expressed on invading pathogens or released from damaged cells. Although it is well known that DAMPs directly modulate innate immune functions, it is less clear whether DAMPs directly regulate T cell intrinsic function. Members of the sialic acid binding Ig-like lectin (Siglec) family have immunoreceptor tyrosine-based inhibitory motifs (ITIM) or ITIM-like regions in their intracellular domain that negatively regulate immune activation induced by DAMPs. Our previous data suggested that the Siglec- G-CD24 interaction in host APCs plays an important role in the negative regulation of graft-versus host (GVH) responses. However, the T cell autonomous role of Siglec-G in the regulation of T cell responses is not known. Because Siglecs are important negative regulators of immune responses, we tested the hypothesis that the deficiency of Siglec-G in donor T cells would enhance GVHD. To test our hypothesis, we first examined detailed phenotypic analysis of various T cell subsets and activation markers in naïve Siglec-G-/- and wild-type (WT) B6 animals and found similar distribution of naïve, memory, effector and regulatory T cells. In order to examine whether the absence of Siglec-G in donors affects GVHD, WT-BALB/cmice were lethally irradiated (850cGy) and transplanted on day 0 with 5x106 bone marrow and 0.5x106 splenic CD90+ T cells from either syngeneic WT-BALB/c, allogeneic MHC-mismatched WT-B6 or Siglec-G-/- animals. The recipients receiving donor T cells from Siglec-G-/- animals showed a significantly worse survival compared to allogeneic WT-B6 animals (p<0.05). This increased mortality was also associated with more severe GVHD damage in target organs and a higher expansion of activated CD69+, IFN-r+, and IL-17A+ donor T cells in the spleen and target organs. Enhanced GVHD mortality and severity was also observed in MHC mismatched haploidentical matched B6 in to F1models (p<0.05). To explore the mechanism, we tested whether Siglec-G deficiency alters the naïve T cell responses in vitro after allogeneic or non-specific TCR stimulation in the absence of exogenous DAMPs. Interestingly Siglec-G-/- T cells showed similar proliferation in vitro, when compared to WT B6 T cells. In addition, Siglec-G-/- Tregs are equally suppressive in suppression assay and Siglec-G-/- T cells showed severe GVHD even Tregs are depleted in allo-BMT. However, Siglec-G-/- T cells showed a higher proliferation after direct TCR stimulation (CD3/CD28) with addition of DAMP (HMGB-1) when compared to WT T cells in vitro, suggesting direct T cell intrinsic effects. Consistent with this result, allogeneic Siglec-G-/- T cells caused similar mortality compared to WT controls in non-irradiated B6 into F1 model due to the absence of DAMPs from conditioning. To test the critical cellular mechanisms, we examined the function of endogenous Siglec-G ligand, CD24. We utilized BALB/c CD24-/- animals as hosts in same BMT model and found that CD24-/- animals showed an enhanced GVHD mortality and severity when compared to WT animals (p<0.05). To enhance Siglec-G-CD24 axis, we utilized a novel CD24 fusion protein (CD24Fc) in same BMT model and found that CD24 Fc ameliorated GVHD severity and mortality in not only allogeneic WT-B6 animals (p<0.05) but also CD24-/- animals (p<0.05). Next we explored DAMPs regulation by Siglec-G-CD24 axis in GVL. We utilized the same model of CD24Fc treatment but added P815 at the same time of allo-BMT and found that CD24Fc treated animals showed equivalent GVL to non-treated animals, suggesting that regulation of DAMPs with CD24Fc mitigates GVHD with maintaining GVL effect. Collectively our data suggested that the expression of both Siglec-G on donor T cells and CD24 on hosts is critical for controlling GVHD in the context of DAMPs released from conditioning, and represents a novel strategy that CD24Fc can mitigates GVHD with maintaining GVL. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.
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Herwald, Heiko, and Arne Egesten. "On PAMPs and DAMPs." Journal of Innate Immunity 8, no. 5 (2016): 427–28. http://dx.doi.org/10.1159/000448437.
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Aquino-Domínguez, Alba Soledad, María de los Ángeles Romero-Tlalolini, and Sergio Roberto Aguilar-Ruiz. "Los receptores del sistema inmunitario innato." RA RIÓ GUENDARUYUBI 5, no. 15 (May 15, 2022): 4–23. http://dx.doi.org/10.53331/rar.v5i15.2463.
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The innate immune system (IIS) is the first line of defense against infectious agents and the detection of tissue damage. The IIS recognizes a group of molecules essential for the survival of microorganisms, which are called pathogen-associated molecular patterns (PAMPs). In addition, IIS recognizes molecules produced and released by damaged or stressed cells, called damage associated molecular patterns (DAMPs). Both PAMPs and DAMPs are recognized by a group of evolutionarily conserved receptors on IIS cells called pattern recognition receptors (PRRs). The recognition of PAMPs and DAMPs by PRRs present in IIS cells leads to different effects on the immune response, including phagocytosis, production of reactive oxygen species (ROS), and expression of genes related to the production of inflammatory and antiviral mediators. For this reason, PRRs are central elements in IIS to respond to pathogens and tissue damage.
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Matsuoka, K., S. Dave, J. Tilstra, F. Li, R. DeMarco, M. Fink, M. Lotze, and S. Plevy. "PAMPs and DAMPs in IBD." Inflammatory Bowel Diseases 13, supplement (May 2007): 643. http://dx.doi.org/10.1097/00054725-200705001-00003.
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Matsuoka, K., S. Davé, J. Tilstra, F. Li, R. DeMarco, M. Fink, M. Lotze, and S. Plevy. "PAMPs and DAMPs in IBD." Inflammatory Bowel Diseases 13 (May 2007): 643. http://dx.doi.org/10.1097/00054725-200705005-00003.
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Foley, John F. "Blocking DAMPs but not PAMPs." Science Signaling 8, no. 360 (January 20, 2015): ec13-ec13. http://dx.doi.org/10.1126/scisignal.aaa6950.
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Ni, Kaiyuan, Guangxu Lan, Nining Guo, August Culbert, Taokun Luo, Tong Wu, Ralph R. Weichselbaum, and Wenbin Lin. "Nanoscale metal-organic frameworks for x-ray activated in situ cancer vaccination." Science Advances 6, no. 40 (October 2020): eabb5223. http://dx.doi.org/10.1126/sciadv.abb5223.
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Cancer vaccines have been actively pursued to bolster antitumor immunity. Here, we designed nanoscale metal-organic frameworks (nMOFs) as locally activable immunotherapeutics to release danger-associated molecular patterns (DAMPs) and tumor antigens and deliver pathogen-associated molecular patterns (PAMPs) for in situ personalized cancer vaccination. When activated by x-rays, nMOFs effectively generate reactive oxygen species to release DAMPs and tumor antigens while delivering CpG oligodeoxynucleotides as PAMPs to facilitate the maturation of antigen-presenting cells. Together, DAMPs, tumor antigens, and PAMPs expand cytotoxic T cells in tumor-draining lymph nodes to reinvigorate the adaptive immune system for local tumor regression. When treated in combination with an immune checkpoint inhibitor, the local therapeutic effects of nMOF-based vaccines were extended to distant tumors via attenuating T cell exhaustion. Our work demonstrates the potential of nMOFs as x-ray–activable in situ cancer vaccines to awaken the host’s innate and adaptive immune systems for systemic antitumor immunity.
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Olejarz, Wioletta, Dominika Łacheta, Alicja Głuszko, Ewa Migacz, Wojciech Kukwa, Mirosław J. Szczepański, Piotr Tomaszewski, and Grażyna Nowicka. "RAGE and TLRs as Key Targets for Antiatherosclerotic Therapy." BioMed Research International 2018 (August 26, 2018): 1–10. http://dx.doi.org/10.1155/2018/7675286.
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Receptor for advanced glycation end-products (RAGE) and toll-like receptors (TLRs) are the key factors indicating a danger to the organism. They recognize the microbial origin pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). The primary response induced by PAMPs or DAMPs is inflammation. Excessive stimulation of the innate immune system occurs in arterial wall with the participation of effector cells. Persistent adaptive responses can also cause tissue damage and disease. However, inflammation mediated by the molecules innate responses is an important way in which the adaptive immune system protects us from infection. The specific detection of PAMPs and DAMPs by host receptors drives a cascade of signaling that converges at nuclear factor-κB (NF-κB) and interferon regulatory factors (IRFs) and induces the secretion of proinflammatory cytokines, type I interferon (IFN), and chemokines, which promote direct killing of the pathogen. Therefore, signaling of these receptors’ pathways also appear to present new avenue for the modulation of inflammatory responses and to serve as potential novel therapeutic targets for antiatherosclerotic therapy.
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Hirsiger, Stefanie, Hans-Peter Simmen, Clément M. L. Werner, Guido A. Wanner, and Daniel Rittirsch. "Danger Signals Activating the Immune Response after Trauma." Mediators of Inflammation 2012 (2012): 1–10. http://dx.doi.org/10.1155/2012/315941.
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Sterile injury can cause a systemic inflammatory response syndrome (SIRS) that resembles the host response during sepsis. The inflammatory response following trauma comprises various systems of the human body which are cross-linked with each other within a highly complex network of inflammation. Endogenous danger signals (danger-associated molecular patterns; DAMPs; alarmins) as well as exogenous pathogen-associated molecular patterns (PAMPs) play a crucial role in the initiation of the immune response. With popularization of the “danger theory,” numerous DAMPs and PAMPs and their corresponding pathogen-recognition receptors have been identified. In this paper, we highlight the role of the DAMPs high-mobility group box protein 1 (HMGB1), interleukin-1α(IL-1α), and interleukin-33 (IL-33) as unique dual-function mediators as well as mitochondrial danger signals released upon cellular trauma and necrosis.
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Zindel, Joel, and Paul Kubes. "DAMPs, PAMPs, and LAMPs in Immunity and Sterile Inflammation." Annual Review of Pathology: Mechanisms of Disease 15, no. 1 (January 24, 2020): 493–518. http://dx.doi.org/10.1146/annurev-pathmechdis-012419-032847.
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Recognizing the importance of leukocyte trafficking in inflammation led to some therapeutic breakthroughs. However, many inflammatory pathologies remain without specific therapy. This review discusses leukocytes in the context of sterile inflammation, a process caused by sterile (non-microbial) molecules, comprising damage-associated molecular patterns (DAMPs). DAMPs bind specific receptors to activate inflammation and start a highly optimized sequence of immune cell recruitment of neutrophils and monocytes to initiate effective tissue repair. When DAMPs are cleared, the recruited leukocytes change from a proinflammatory to a reparative program, a switch that is locally supervised by invariant natural killer T cells. In addition, neutrophils exit the inflammatory site and reverse transmigrate back to the bloodstream. Inflammation persists when the program switch or reverse transmigration fails, or when the coordinated leukocyte effort cannot clear the immunostimulatory molecules. The latter causes inappropriate leukocyte activation, a driver of many pathologies associated with poor lifestyle choices. We discuss lifestyle-associated inflammatory diseases and their corresponding immunostimulatory lifestyle-associated molecular patterns (LAMPs) and distinguish them from DAMPs.
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Rai, Vikrant, and Devendra K. Agrawal. "The role of damage- and pathogen-associated molecular patterns in inflammation-mediated vulnerability of atherosclerotic plaques." Canadian Journal of Physiology and Pharmacology 95, no. 10 (October 2017): 1245–53. http://dx.doi.org/10.1139/cjpp-2016-0664.
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Atherosclerosis is a chronic inflammatory disease resulting in the formation of the atherosclerotic plaque. Plaque formation starts with the inflammation in fatty streaks and progresses through atheroma, atheromatous plaque, and fibroatheroma leading to development of stable plaque. Hypercholesterolemia, dyslipidemia, and hyperglycemia are the risk factors for atherosclerosis. Inflammation, infection with viruses and bacteria, and dysregulation in the endothelial and vascular smooth muscle cells leads to advanced plaque formation. Death of the cells in the intima due to inflammation results in secretion of damage-associated molecular patterns (DAMPs) such as high mobility group box 1 (HMGB1), receptor for advanced glycation end products (RAGE), alarmins (S100A8, S100A9, S100A12, and oxidized low-density lipoproteins), and infection with pathogens leads to secretion of pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharides, lipoteichoic acids, and peptidoglycans. DAMPs and PAMPs further activate the inflammatory surface receptors such as TREM-1 and toll-like receptors and downstream signaling kinases and transcription factors leading to increased secretion of pro-inflammatory cytokines such as tumor necrosis factor α, interleukin (IL)-1β, IL-6, and interferon-γ and matrix metalloproteinases (MMPs). These mediators and cytokines along with MMPs render the plaque vulnerable for rupture leading to ischemic events. In this review, we have discussed the role of DAMPs and PAMPs in association with inflammation-mediated plaque vulnerability.
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Fischer, Silvia, and Elisabeth Deindl. "State of the Art of Innate Immunity—An Overview." Cells 11, no. 17 (August 30, 2022): 2705. http://dx.doi.org/10.3390/cells11172705.
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The innate immune system is the first line of defense against bacterial and viral infections and sterile inflammation through the recognition of pathogen-associated molecular patterns (PAMPs) as well as danger-associated molecular patterns (DAMPs) by pathogen-recognition receptors (PRRs), and produces proinflammatory and antiviral cytokines and chemokines [...]
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ITO, Takashi. "PAMPs/DAMPs as novel mediators of inflammation-associated thrombosis." Japanese Journal of Thrombosis and Hemostasis 24, no. 6 (2013): 675–79. http://dx.doi.org/10.2491/jjsth.24.675.
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Chain, Robert, Linda Varghese, and Stefania Gallucci. "Role of PAMPs and DAMPs in Graft Rejection (126.6)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 126.6. http://dx.doi.org/10.4049/jimmunol.188.supp.126.6.
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Abstract Dendritic cells (DCs) induce immunity or tolerance depending on the presence of danger signals. LPS is a danger signal with multiple effects on DCs, besides activation. Unpublished results from our lab show that LPS induces DC death in vitro and in vivo. It has also been reported that DCs treated with LPS during their development remained immature and induced T cell anergy. LPS triggers TLR4, a PRR also stimulated by endogenous danger signals, like HMGB1, released during tissue damage. We used a mouse transplant model to determine the effects of simultaneous exposure to LPS and endogenous danger signals, released during engraftment, on DC functions and graft survival. We used the single minor male-specific H-Y antigen mismatch. We transplanted skin of male C57BL/6 mice onto syngeneic female recipients. We administered 4 i.p. injections of 12.5ug/mouse of LPS or PBS every other day. Control mice rejected male skin graft in 24-34 days, as expected, while mice treated with LPS did not reject the graft until 64 days or later. Studying the DCs migrating out of the graft, we found a sharp decrease of DCs 48 hours post transplant and the DC loss was more severe after LPS. LPS also decreased the number of DCs with high surface expression of MHC class II. These findings suggest that the combination of endogenous danger signals released during engraftment and LPS are either killing the DCs or preventing them from maturing thus allowing for tolerance of the male skin graft.
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Markus, Regina P., Kassiano S. Sousa, Sanseray da Silveira Cruz-Machado, Pedro A. Fernandes, and Zulma S. Ferreira. "Possible Role of Pineal and Extra-Pineal Melatonin in Surveillance, Immunity, and First-Line Defense." International Journal of Molecular Sciences 22, no. 22 (November 10, 2021): 12143. http://dx.doi.org/10.3390/ijms222212143.
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Melatonin is a highly conserved molecule found in prokaryotes and eukaryotes that acts as the darkness hormone, translating environmental lighting to the whole body, and as a moderator of innate and acquired defense, migration, and cell proliferation processes. This review evaluates the importance of pineal activity in monitoring PAMPs and DAMPs and in mounting an inflammatory response or innate immune response. Activation of the immune–pineal axis, which coordinates the pro-and anti-inflammatory phases of an innate immune response, is described. PAMPs and DAMPs promote the immediate suppression of melatonin production by the pineal gland, which allows leukocyte migration. Monocyte-derived macrophages, important phagocytes of microbes, and cellular debris produce melatonin locally and thereby initiate the anti-inflammatory phase of the acute inflammatory response. The role of locally produced melatonin in organs that directly contact the external environment, such as the skin and the gastrointestinal and respiratory tracts, is also discussed. In this context, as resident macrophages are self-renewing cells, we explore evidence indicating that, besides avoiding overreaction of the immune system, extra-pineal melatonin has a fundamental role in the homeostasis of organs and tissues.
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Li, Sicheng, Qiongyuan Hu, Jinjian Huang, Xiuwen Wu, and Jianan Ren. "Mitochondria-Derived Damage-Associated Molecular Patterns in Sepsis: From Bench to Bedside." Oxidative Medicine and Cellular Longevity 2019 (May 8, 2019): 1–9. http://dx.doi.org/10.1155/2019/6914849.
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Sepsis is one of the most serious health hazards. Current research suggests that the pathogenesis of sepsis is mediated by both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Mitochondria are among the most important organelles in cells and determine their life and death. A variety of mitochondria-derived DAMPs (mtDAMPs) are similar to bacteria because mitochondria are derived from bacteria according to the mitochondrial endosymbiotic theory. Their activated signaling pathways extensively affect organ functions, the immune system, and metabolic functions in sepsis. In this review, we describe the essential roles of mtDAMPs in sepsis and discuss their research prospects and clinical importance.
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Tang, Daolin, Rui Kang, Carolyn B. Coyne, Herbert J. Zeh, and Michael T. Lotze. "PAMPs and DAMPs: signal 0s that spur autophagy and immunity." Immunological Reviews 249, no. 1 (August 14, 2012): 158–75. http://dx.doi.org/10.1111/j.1600-065x.2012.01146.x.
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Gentile, Lori F., and Lyle L. Moldawer. "DAMPs, PAMPs, and the Origins of SIRS in Bacterial Sepsis." Shock 39, no. 1 (January 2013): 113–14. http://dx.doi.org/10.1097/shk.0b013e318277109c.
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Holl, Eda K., Kara L. Shumansky, Luke B. Borst, Angela D. Burnette, Christopher J. Sample, Elizabeth A. Ramsburg, and Bruce A. Sullenger. "Scavenging nucleic acid debris to combat autoimmunity and infectious disease." Proceedings of the National Academy of Sciences 113, no. 35 (August 15, 2016): 9728–33. http://dx.doi.org/10.1073/pnas.1607011113.
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Nucleic acid-containing debris released from dead and dying cells can be recognized as damage-associated molecular patterns (DAMPs) or pattern-associated molecular patterns (PAMPs) by the innate immune system. Inappropriate activation of the innate immune response can engender pathological inflammation and autoimmune disease. To combat such diseases, major efforts have been made to therapeutically target the pattern recognition receptors (PRRs) such as the Toll-like receptors (TLRs) that recognize such DAMPs and PAMPs, or the downstream effector molecules they engender, to limit inflammation. Unfortunately, such strategies can limit the ability of the immune system to combat infection. Previously, we demonstrated that nucleic acid-binding polymers can act as molecular scavengers and limit the ability of artificial nucleic acid ligands to activate PRRs. Herein, we demonstrate that nucleic acid scavengers (NASs) can limit pathological inflammation and nucleic acid-associated autoimmunity in lupus-prone mice. Moreover, we observe that such NASs do not limit an animal’s ability to combat viral infection, but rather their administration improves survival when animals are challenged with lethal doses of influenza. These results indicate that molecules that scavenge extracellular nucleic acid debris represent potentially safer agents to control pathological inflammation associated with a wide range of autoimmune and infectious diseases.
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Sun, Lixiang, Wenjie Liu, and Ling-juan Zhang. "The Role of Toll-Like Receptors in Skin Host Defense, Psoriasis, and Atopic Dermatitis." Journal of Immunology Research 2019 (November 14, 2019): 1–13. http://dx.doi.org/10.1155/2019/1824624.
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As the key defense molecules originally identified in Drosophila, Toll-like receptor (TLR) superfamily members play a fundamental role in detecting invading pathogens or damage and initiating the innate immune system of mammalian cells. The skin, the largest organ of the human body, protects the human body by providing a critical physical and immunological active multilayered barrier against invading pathogens and environmental factors. At the first line of defense, the skin is constantly exposed to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), and TLRs, expressed in a cell type-specific manner by various skin cells, serve as key molecules to recognize PAMPs and DAMPs and to initiate downstream innate immune host responses. While TLR-initiated inflammatory responses are necessary for pathogen clearance and tissue repair, aberrant activation of TLRs will exaggerate T cell-mediated autoimmune activation, leading to unwanted inflammation, and the development of several skin diseases, including psoriasis, atopic dermatitis, systemic lupus erythematosus, diabetic foot ulcers, fibrotic skin diseases, and skin cancers. Together, TLRs are at the interface between innate immunity and adaptive immunity. In this review, we will describe current understanding of the role of TLRs in skin defense and in the pathogenesis of psoriasis and atopic dermatitis, and we will also discuss the development and therapeutic effect of TLR-targeted therapies.
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ITO, Takashi, and Ikuro MARUYAMA. "Thrombus formation and innate immunity." Japanese Journal of Thrombosis and Hemostasis 23, no. 3 (2012): 241–46. http://dx.doi.org/10.2491/jjsth.23.241.
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Bianchi, Marco E. "DAMPs, PAMPs and alarmins: all we need to know about danger." Journal of Leukocyte Biology 81, no. 1 (October 10, 2006): 1–5. http://dx.doi.org/10.1189/jlb.0306164.
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Hughes, Francis M., Nivardo P. Vivar, James G. Kennis, Jeffery D. Pratt-Thomas, Danielle W. Lowe, Brooke E. Shaner, Paul J. Nietert, Laura S. Spruill, and J. Todd Purves. "Inflammasomes are important mediators of cyclophosphamide-induced bladder inflammation." American Journal of Physiology-Renal Physiology 306, no. 3 (February 1, 2014): F299—F308. http://dx.doi.org/10.1152/ajprenal.00297.2013.
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Bladder inflammation (cystitis) underlies numerous bladder pathologies and is elicited by a plethora of agents such as urinary tract infections, bladder outlet obstruction, chemotherapies, and catheters. Pattern recognition receptors [Toll-like receptors (TLRs) and Nod-like receptors (NLRs)] that recognize pathogen- and/or damage-associated molecular patterns (PAMPs and/or DAMPs, respectively) are key components of the innate immune system that coordinates the production (TLRs) and maturation (NLRs) of proinflammatory IL-1β. Despite multiple studies of TLRs in the bladder, none have investigated NLRs beyond one small survey. We now demonstrate that NLRP3 and NLRC4, and their binding partners apoptosis-associated speck-like protein containing a COOH-terminal caspase recruitment domain (ASC) and NLR family apoptosis inhibitory protein (NAIP), are expressed in the bladder and localized predominantly to the urothelia. Activated NLRs form inflammasomes that activate caspase-1. Placement of a NLRP3- or NLRC4-activating PAMP or NLRP3-activating DAMPs into the lumen of the bladder stimulated caspase-1 activity. To investigate inflammasomes in vivo, we induced cystitis with cyclophosphamide (CP, 150 mg/kg ip) in the presence or absence of the inflammasome inhibitor glyburide. Glyburide completely blocked CP-induced activation of caspase-1 and the production of IL-1β at 4 h. At 24 h, glyburide reduced two markers of inflammation by 30–50% and reversed much of the inflammatory morphology. Furthermore, glyburide reversed changes in bladder physiology (cystometry) induced by CP. In conclusion, NLRs/inflammasomes are present in the bladder urothelia and respond to DAMPs and PAMPs, whereas NLRP3 inhibition blocks bladder dysfunction in the CP model. The coordinated response of NLRs and TLRs in the urothelia represents a first-line innate defense that may provide an important target for pharmacological intervention.
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Krakauer, Teresa. "Inflammasomes, Autophagy, and Cell Death: The Trinity of Innate Host Defense against Intracellular Bacteria." Mediators of Inflammation 2019 (January 8, 2019): 1–10. http://dx.doi.org/10.1155/2019/2471215.
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Inflammasome activation is an innate host defense mechanism initiated upon sensing pathogens or danger in the cytosol. Both autophagy and cell death are cell autonomous processes important in development, as well as in host defense against intracellular bacteria. Inflammasome, autophagy, and cell death pathways can be activated by pathogens, pathogen-associated molecular patterns (PAMPs), cell stress, and host-derived damage-associated molecular patterns (DAMPs). Phagocytosis and toll-like receptor (TLR) signaling induce reactive oxygen species (ROS), type I IFN, NFκB activation of proinflammatory cytokines, and the mitogen-activated protein kinase cascade. ROS and IFNγare also prominent inducers of autophagy. Pathogens, PAMPs, and DAMPs activate TLRs and intracellular inflammasomes, inducing apoptotic and inflammatory caspases in a context-dependent manner to promote various forms of cell death to eliminate pathogens. Common downstream signaling molecules of inflammasomes, autophagy, and cell death pathways interact to initiate appropriate measures against pathogens and determine host survival as well as pathological consequences of infection. The integration of inflammasome activation, autophagy, and cell death is central to pathogen clearance. Various pathogens produce virulence factors to control inflammasomes, subvert autophagy, and modulate host cell death in order to evade host defense. This review highlights the interaction of inflammasomes, autophagy, and host cell death pathways in counteractingBurkholderia pseudomallei, the causative agent of melioidosis. Contrasting evasion strategies used byB.pseudomallei,Mycobacterium tuberculosis, andLegionella pneumophilato avoid and dampen these innate immune responses will be discussed.
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Evankovich, John, Timothy Billiar, and Allan Tsung. "Toll-Like Receptors in Hepatic Ischemia/Reperfusion and Transplantation." Gastroenterology Research and Practice 2010 (2010): 1–8. http://dx.doi.org/10.1155/2010/537263.
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The family of Toll-like receptors (TLRs) function as pattern-recognition receptors (PRRs) that respond to a myriad of highly conserved ligands. These substrates include pathogen-associated molecular patterns (PAMPs) for the recognition of invading pathogens, as well as damage-associated molecular patterns (DAMPs) for the recognition of endogenous tissue injury. While the functions of TLRs are diverse, they have received much attention for their roles in ischemia/reperfusion (I/R) injury of the liver and other organs. The TLRs play central roles in sensing tissue damage and activating the innate immune system following I/R. Engagement of TLRs by endogenous DAMPs activates proinflammatory signaling pathways leading to the production of cytokines, chemokines and further release of endogenous danger signals. This paper focuses on the most recent findings regarding TLR family members in hepatic I/R injury and transplantation.
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Pisetsky, David S. "The origin and properties of extracellular DNA: From PAMP to DAMP." Clinical Immunology 144, no. 1 (July 2012): 32–40. http://dx.doi.org/10.1016/j.clim.2012.04.006.
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Sundaram, Balamurugan, and Thirumala-Devi Kanneganti. "Advances in Understanding Activation and Function of the NLRC4 Inflammasome." International Journal of Molecular Sciences 22, no. 3 (January 21, 2021): 1048. http://dx.doi.org/10.3390/ijms22031048.
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Innate immune receptors initiate a host immune response, or inflammatory response, upon detecting pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Among the innate immune receptors, nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) play a pivotal role in detecting cytosolic PAMPs and DAMPs. Some NLRs can form a multiprotein cytosolic complex known as the inflammasome. Inflammasome activation triggers caspase-1–mediated cleavage of the pore-forming protein gasdermin D (GSDMD), which drives a form of inflammatory cell death called pyroptosis. Parallelly, activated caspase-1 cleaves immature cytokines pro–IL-1β and pro–IL-18 into their active forms, which can be released via GSDMD membrane pores. The NLR family apoptosis inhibitory proteins (NAIP)-NLR family caspase-associated recruitment domain-containing protein 4 (NLRC4) inflammasome is important for mounting an immune response against Gram-negative bacteria. NLRC4 is activated through NAIPs sensing type 3 secretion system (T3SS) proteins from Gram-negative bacteria, such as Salmonella Typhimurium. Mutations in NAIPs and NLRC4 are linked to autoinflammatory disorders in humans. In this review, we highlight the role of the NAIP/NLRC4 inflammasome in host defense, autoinflammatory diseases, cancer, and cell death. We also discuss evidence pointing to a role of NLRC4 in PANoptosis, which was recently identified as a unique inflammatory programmed cell death pathway with important physiological relevance in a range of diseases. Improved understanding of the NLRC4 inflammasome and its potential roles in PANoptosis paves the way for identifying new therapeutic strategies to target disease.
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Wilson, Carole L., Sarah E. Stephenson, Jean Paul Higuero, Carol Feghali-Bostwick, Chi F. Hung, and Lynn M. Schnapp. "Characterization of human PDGFR-β-positive pericytes from IPF and non-IPF lungs." American Journal of Physiology-Lung Cellular and Molecular Physiology 315, no. 6 (December 1, 2018): L991—L1002. http://dx.doi.org/10.1152/ajplung.00289.2018.
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Pericytes are key regulators of the microvasculature through their close interactions with the endothelium. However, pericytes play additional roles in tissue homeostasis and repair, in part by transitioning into myofibroblasts. Accumulation of myofibroblasts is a hallmark of fibrotic diseases such as idiopathic pulmonary fibrosis (IPF). To understand the contribution and role of pericytes in human lung fibrosis, we isolated these cells from non-IPF control and IPF lung tissues based on expression of platelet-derived growth factor receptor-β (PDGFR-β), a common marker of pericytes. When cultured in a specialized growth medium, PDGFR-β+ cells retain the morphology and marker profile typical of pericytes. We found that IPF pericytes migrated more rapidly and invaded a basement membrane matrix more readily than control pericytes. Exposure of cells to transforming growth factor-β, a major fibrosis-inducing cytokine, increased expression of α-smooth muscle actin and extracellular matrix genes in both control and IPF pericytes. Given that pericytes are uniquely positioned in vivo to respond to danger signals of both systemic and tissue origin, we stimulated human lung pericytes with agonists having pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). Both control and IPF lung pericytes increased expression of proinflammatory chemokines in response to specific PAMPs and DAMPs released from necrotic cells. Our results suggest that control and IPF lung pericytes are poised to react to tissue damage, as well as microbial and fibrotic stimuli. However, IPF pericytes are primed for migration and matrix invasion, features that may contribute to the function of these cells in lung fibrosis.