Journal articles on the topic 'ST2 expression in asthma'
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1
Ramirez-Carrozzi, Vladimir, Amy Dressen, Patrick Lupardus, Brian Yaspan, and Rajita Pappu. "Functional analysis of protective IL1RL1 variants associated with asthma risk (CCR6P.215)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 187.2. http://dx.doi.org/10.4049/jimmunol.194.supp.187.2.
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Abstract GWAS studies have identified polymorphisms in both IL33 and IL1RL1, the gene encoding ST2, the high affinity chain of the IL-33 receptor, that associate with asthma susceptibility. We identified amino acid changing variants in IL1RL1 associating with asthma incidence and found these SNPs to be protective from asthma risk in our study population. These variants result in coding changes to the intracellular region of ST2, which contains the TIR domain of the receptor that is critical for signaling downstream of IL-1 cytokine family and TLRs. Mutations or deletions to this region can inhibit ligand-induced responses. IL-33-mediated dimerization of ST2 and IL-1RAcP promotes TIR-TIR domain interaction and recruitment of the adaptor molecule MyD88 leading to AP-1 and NF-kB activation. IL-33 responses were diminished in cell lines expressing all 4 IL1RL1 missense variants. To further elucidate how this haplotype could affect IL-33 activity, we compared IL-33 activity and ST2 expression between donors carrying either haplotype. We observed reduced IL-33 mediated IL-8 secretion from purified blood eosinophils derived from individuals carrying the protective haplotype. We also observed greater soluble ST2 expression in these individuals. Our results provide a link between the genetic predisposition to asthma and IL-33 mediated responses. Given IL-33 promotes Th2 immunity, perturbations that diminish this response may provide protection from asthma risk.
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Kaur, Davinder, Latifa Chachi, Edith Gomez, Nicolas Sylvius, Shailendra R. Singh, Mohammadali Y. Ramsheh, Ruth Saunders, and Christopher E. Brightling. "ST2 expression and release by the bronchial epithelium is downregulated in asthma." Allergy 75, no. 12 (July 27, 2020): 3184–94. http://dx.doi.org/10.1111/all.14436.
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Taruselli, Marcela T., Amina Abdul Qayum, and John J. Ryan. "MicroRNA-146a is a negative regulator of IL-33 stimulated mouse mast cells." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 105.16. http://dx.doi.org/10.4049/jimmunol.200.supp.105.16.
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Abstract Interleukin 33 (IL-33) is an inflammatory cytokine that promotes allergic disease by activating ILC2, Th2 cells, and mast cells. IL-33 is increased in asthmatics, and its blockade suppresses asthma-like inflammation in mouse models. The IL-33 receptor, ST2, shares signaling cascades with the TLR family, but homeostatic control of ST2 function is poorly understood. MicroRNA-146a (miR-146a) is induced by LPS and suppresses TLR4 signaling in macrophages. Therefore, we explored whether miR-146a has a role in IL-33 signaling. IL-33 induced cellular and exosomal miR-146a expression in mouse bone marrow derived mast cells (BMMC). Induction required MyD88, Akt, and NFκB, since antagonizing these pathways decreased miR-146 expression. BMMC transfected with a miR-146a antagomir or derived from miR-146a KO mice showed enhanced cytokine expression in response to IL-33, suggesting that mir46a is a negative regulator of IL-33-ST2 signaling. Our data further suggest that miR-146a may act by targeting IRAK proteins, because mir146a KO BMMC have increased IRAK1 and IRAK4 expression. These results support the hypothesis that miR-146a is a feedback regulator of IL-33-mediated mast cell functions associated with allergic disease.
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Kee, Sydney Ann, Marcela T. Taruselli, John J. Ryan, and Amina Abdul Qayum. "MiR-146a is a negative regulator of IL-33-stimulated mouse mast cells." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 185.5. http://dx.doi.org/10.4049/jimmunol.202.supp.185.5.
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Abstract Interleukin-33 (IL-33) is an inflammatory cytokine that promotes allergic disease by activating ILC2, Th2, and mast cells. IL-33 is increased in asthmatics, and its blockade suppresses asthma-like inflammation in mouse models. The IL-33 receptor, ST2, shares signaling cascades with the TLR family, but homeostatic control of ST2 function is poorly understood. MicroRNA-146a (miR-146a) is induced by LPS and suppresses TLR4 signaling in macrophages. Therefore, we explored whether miR-146a has a role in IL-33 signaling. IL-33 induced cellular and exosomal miR-146a expression in mouse bone marrow derived mast cells (BMMC). Induction required MyD88, Akt, and NFkB, since antagonizing these pathways decreased miR-146 expression. BMMC transfected with a miR-146a antagomir or derived from miR-146a KO mice showed enhanced cytokine expression in response to IL-33, suggesting that miR-146a is a negative regulator of IL-33-ST2 signaling. Our data further suggest that miR-146a may act by targeting IRAK proteins, because mir-146a KO BMMC have increased TRAF6, IRAK1, and IRAK4 expression. In vivo, miR-146a expression in plasma exosomes was elevated after intraperitoneal injection of IL-33. Also mast cell deficient c-Kitw-sh mice acutely reconstituted with miR-146a KO BMMC intraperitoneally had elevated plasma IL-6 levels in comparison to their WT counterparts after IL-33 challenge. These results support the hypothesis that miR-146a is a feedback regulator of IL-33-mediated mast cell functions associated with allergic disease.
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Johnston, Laura K., Chia-Lin Hsu, Rebecca A. Krier-Burris, Krishan D. Chhiba, Karen B. Chien, Andrew McKenzie, Sergejs Berdnikovs, and Paul J. Bryce. "Eosinophil lineage commitment and IL-5-dependent expansion is regulated by IL-33 in mice." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 191.7. http://dx.doi.org/10.4049/jimmunol.196.supp.191.7.
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Abstract Eosinophils are important in the pathogenesis of many diseases, including asthma, eosinophilic esophagitis and eczema. While IL-5 is necessary for the maturation of eosinophil progenitors (EoP) into mature eosinophils (EoM), the signals that promote commitment to the eosinophil lineage are unknown. The IL-33 receptor, ST2, is expressed on several inflammatory cells, including eosinophils, and is best characterized for its role during the initiation of allergic responses in the peripheral tissues. Recently, ST2 expression was described on hematopoietic stem cells, where its function remains unclear. Here, we sought to determine whether IL-33 and ST2 contribute to hematopoietic lineage decisions. We found that both IL-33- and ST2-deficient mice exhibited diminished peripheral blood eosinophils at baseline. Correspondingly, IL-33 administration increased EoM as well as IL-5 in the blood and bone marrow in WT and IL-33-deficient but not ST2-deficient mice. Blocking IL-5 with a neutralizing antibody prevented IL-33-expanded EoP from maturing into EoM, while transgenic overexpression of IL-5 in ST2-deficient mice resulted in significantly lower hypereosinophilia than transgenic IL-5 mice. Finally, we observed that IL-33, but not IL-5, specifically expanded EoP and upregulated IL-5Rα on EoP as well as increased IL-5 after bone marrow was cultured for three days. Our findings identify a basal defect in eosinophilopoiesis in IL-33- and ST2-deficient mice. Furthermore, we establish unappreciated roles for IL-33 and ST2 in eosinophil development via progenitor regulation and define a mechanism whereby IL-33 licenses commitment into the eosinophil lineage by driving both responsiveness to IL-5 and IL-5 production.
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Paplinska-Goryca, Magdalena, Paulina Misiukiewicz-Stepien, Malgorzata Proboszcz, Patrycja Nejman-Gryz, Katarzyna Gorska, and Rafal Krenke. "The Expressions of TSLP, IL-33, and IL-17A in Monocyte Derived Dendritic Cells from Asthma and COPD Patients are Related to Epithelial–Macrophage Interactions." Cells 9, no. 9 (August 22, 2020): 1944. http://dx.doi.org/10.3390/cells9091944.
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Background. The cross-talk between the external and internal environment in the respiratory tract involves macrophage/dendritic cell (DC) transepithelial network. Epithelium triggers dendritic cell-mediated inflammation by producing thymic stromal lymphopoietin (TSLP), IL-33, and IL-17A. The study aimed to evaluate the expression of TSLP, IL-33, and IL-17A in human monocyte derived dendritic cells (moDCs) co-cultured with respiratory epithelium and monocyte derived macrophages (moMφs) in asthma, chronic obstructive pulmonary disease (COPD) and healthy controls. Methods. The study used a triple-cell co-culture model, utilizing nasal epithelial cells, along with moMφs and moDCs. Cells were cultured in mono-, di-, and triple-co-cultures for 24 h. Results. Co-culture with epithelium and moMφs significantly increased TSLP in asthma and did not change IL-33 and IL-17A mRNA expression in moDCs. moDCs from asthmatics were characterized by the highest TSLP mRNA expression and the richest population of TSLPR, ST2, and IL17RA expressed cells. A high number of positive correlations between the assessed cytokines and CHI3L1, IL-12p40, IL-1β, IL-6, IL-8, TNF in moDCs was observed in asthma and COPD. Conclusion. TSLP, IL-33, and IL-17A expression in moDCs are differently regulated by epithelium in asthma, COPD, and healthy subjects. These complex cell–cell interactions may impact airway inflammation and be an important factor in the pathobiology of asthma and COPD.
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Boberg, Emma, Kristina Johansson, Carina Malmhäll, Julie Weidner, and Madeleine Rådinger. "House Dust Mite Induces Bone Marrow IL-33-Responsive ILC2s and TH Cells." International Journal of Molecular Sciences 21, no. 11 (May 26, 2020): 3751. http://dx.doi.org/10.3390/ijms21113751.
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Type 2 innate lymphoid cells (ILC2s) and their adaptive counterpart type 2 T helper (TH2) cells respond to interleukin-33 (IL-33) by producing IL-5, which is a crucial cytokine for eosinophil development in the bone marrow. The aim of this study was to determine if bone marrow ILC2s, TH cells, and eosinophils are locally regulated by IL-33 in terms of number and activation upon exposure to the common aeroallergen house dust mite (HDM). Mice that were sensitized and challenged with HDM by intranasal exposures induced eosinophil development in the bone marrow with an initial increase of IL5Rα+ eosinophil progenitors, following elevated numbers of mature eosinophils and the induction of airway eosinophilia. Bone marrow ILC2s, TH2, and eosinophils all responded to HDM challenge by increased IL-33 receptor (ST2) expression. However, only ILC2s, but not TH cells, revealed increased ST2 expression at the onset of eosinophil development, which significantly correlated with the number of eosinophil progenitors. In summary, our findings suggest that airway allergen challenges with HDM activates IL-33-responsive ILC2s, TH cells, and eosinophils locally in the bone marrow. Targeting the IL-33/ST2 axis in allergic diseases including asthma may be beneficial by decreasing eosinophil production in the bone marrow.
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Ota, Kyoko, Mio Kawaguchi, Satoshi Matsukura, Masatsugu Kurokawa, Fumio Kokubu, Junichi Fujita, Yuko Morishima, et al. "Potential Involvement of IL-17F in Asthma." Journal of Immunology Research 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/602846.
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The expression of IL-17F is seen in the airway of asthmatics and its level is correlated with disease severity. Several studies have demonstrated that IL-17F plays a pivotal role in allergic airway inflammation and induces several asthma-related molecules such as CCL20. IL-17F-induced CCL20 may attract Th17 cells into the airway resulting in the recruitment of additional Th17 cells to enhance allergic airway inflammation. We have recently identified, for the first time, that bronchial epithelial cells are its novel cell source in response to IL-33 via ST2-ERK1/2-MSK1 signaling pathway. The receptor for IL-17F is the heterodimeric complex of IL-17RA and IL-17RC, and IL-17F activates many signaling pathways. In a case-control study of 867 unrelated Japanese subjects, a His161 to Arg161 (H161R) substitution in the third exon of the IL-17F gene was associated with asthma. In atopic patients with asthma, prebronchodilator baseline FEV1/FVC values showed a significant association with the H161R variant. Moreover, this variant is a natural antagonist for the wild-type IL-17F. Moreover, IL-17F is involved in airway remodeling and steroid resistance. Hence, IL-17F may play an orchestrating role in the pathogenesis of asthma and may provide a valuable therapeutic target for development of novel strategies.
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Ferrini, Maria M., Zeina Jaffar, and Kevan Roberts. "Critical role for IL-33 in orchestrating group 2 innate lymphoid cell and natural killer cell function in the lungs." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 119.28. http://dx.doi.org/10.4049/jimmunol.202.supp.119.28.
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Abstract The alarmin, IL-33, acting via ST2 receptors initiates innate immunity to inhaled allergens and environmental particulates. IL-33 belongs to the IL-1 family and is largely derived from epithelial cells, endothelial cells and fibroblasts. The cytokine plays a critical role in underpinning type 2 immunity at mucosal sites and the IL-33/ST2 axis has been implicated in bronchial asthma and virus-induced exacerbations of allergic airway disease. In this study, we found that IL-33 instillations into the airways of C57BL/6 mice, for 3 days over a 7 day period, induced a marked increase in the number of group 2 innate lymphoid cells (ILC2s) and their production of type 2 cytokines IL-13 and IL-5 and this was associated with a pronounced pulmonary eosinophilic inflammation and airway mucus production. Interestingly, IL-33 administration also resulted in an increase in the number of CD11b+CD11C+MHCII+ dendritic cells and evoked a marked expansion of Th2 cells in the lung mucosa. Concomitant with this response, there was a significant reduction in IFN-γ production by pulmonary CD3−CD19−DX5+NK1.1+ NK cells. Flow cytometry revealed that ST2 expression was predominantly expressed by pulmonary ILC2s rather than NK cells, raising the possibility that ILC2s, either directly or indirectly, regulate the NK cell response. These findings reveal that IL-33 plays critical roles in both initiating pulmonary innate and adaptive immune responses, thus providing an essential axis for rapid immune responses and tissue homeostasis in the lung as well as influencing the development of chronic airway inflammation and remodeling.
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Bachert, Claus, Marc Humbert, Nicola A. Hanania, Nan Zhang, Stephen Holgate, Roland Buhl, and Barbara M. Bröker. "Staphylococcus aureus and its IgE-inducing enterotoxins in asthma: current knowledge." European Respiratory Journal 55, no. 4 (January 24, 2020): 1901592. http://dx.doi.org/10.1183/13993003.01592-2019.
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While immunoglobulin (Ig) E is a prominent biomarker for early-onset, its levels are often elevated in non-allergic late-onset asthma. However, the pattern of IgE expression in the latter is mostly polyclonal, with specific IgEs low or below detection level albeit with an increased total IgE. In late-onset severe asthma patients, specific IgE to Staphylococcal enterotoxins (se-IgE) can frequently be detected in serum, and has been associated with asthma, with severe asthma defined by hospitalisations, oral steroid use and decrease in lung function. Recently, se-IgE was demonstrated to even predict the development into severe asthma with exacerbations over the next decade. Staphylococcus aureus manipulates the airway mucosal immunology at various levels via its proteins, including superantigens, serine-protease-like proteins (Spls), or protein A (SpA) and possibly others. Release of IL-33 from respiratory epithelium and activation of innate lymphoid cells (ILCs) via its receptor ST2, type 2 cytokine release from those ILCs and T helper (Th) 2 cells, mast cell degranulation, massive local B-cell activation and IgE formation, and finally eosinophil attraction with consequent release of extracellular traps, adding to the epithelial damage and contributing to disease persistence via formation of Charcot–Leyden crystals are the most prominent hallmarks of the manipulation of the mucosal immunity by S. aureus. In summary, S. aureus claims a prominent role in the orchestration of severe airway inflammation and in current and future disease severity. In this review, we discuss current knowledge in this field and outline the needs for future research to fully understand the impact of S. aureus and its proteins on asthma.
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Guo, Hui, Ling Huang, Na Tang, Kody Waldstein, Steven M. Varga, and Jian Zhang. "E3 Ubiquitin Ligase Cbl-b Inhibits Type 2 Innate Lymphoid Cell Development by Targeting ST2 for Ubiquitination." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 147.25. http://dx.doi.org/10.4049/jimmunol.204.supp.147.25.
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Abstract Type 2 innate lymphoid cells (ILC2) play a crucial role in driving allergic airway inflammation, but the regulation of ILC2 development is not fully understood. Previously we have shown that E3 ubiquitin ligase Cbl-b negatively regulates Th2 response, but whether Cbl-b also regulates ILC2-mediated type 2 immunity remains to be defined. In this study, we found that Rag1−/−Cblb−/− mice are hypersensitive to inhalation of A. Fumigatus, a fungus that causes allergic asthma, as revealed by heightened airway hyperresponsiveness (AHR), increased airway inflammation, and mucus production. This hypersensitivity is associated with increased frequencies of ILC2 and eosinophils, but reduced frequency of alveolar macrophages in the lungs. Consistent with this, type 2 cytokines are also increased in the lung homogenates of Rag1−/−Cblb−/− mice. At the molecular levels, ST2 undergoes ubiquitination and proteasome-mediated degradation upon IL-33 stimulation, which is abrogated in cells expressing Cbl-b C373A mutant. Therefore, our data indicate that Cbl-b inhibits the development of ILC2 and ILC2-mediated airway inflammation by targeting ST2 for ubiquitination.
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Guo, Hui, Ling Huang, Kody Waldstein, Steven M. Varga, and Jian Zhang. "E3 Ubiquitin Ligase Cbl-b Inhibits Type 2 Innate Lymphoid Cell Development by Targeting ST2 for Ubiquitination." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 109.13. http://dx.doi.org/10.4049/jimmunol.208.supp.109.13.
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Abstract Type 2 innate lymphoid cells (ILC2) play a crucial role in driving allergic airway inflammation, but the regulation of ILC2 development is not fully understood. Previously we have shown that E3 ubiquitin ligase Cbl-b negatively regulates Th2 response, but whether Cbl-b also regulates ILC2-mediated type 2 immunity remains to be defined. In this study, we found that Rag1−/−Cblb−/− mice are hypersensitive to inhalation of A. Fumigatus, a fungus that causes allergic asthma, as revealed by heightened airway hyperresponsiveness (AHR), increased airway inflammation, and mucus production. This hypersensitivity is associated with increased frequencies of ILC2 and eosinophils, but reduced frequency of alveolar macrophages in the lungs. Consistent with this, type 2 cytokines are also increased in the lung homogenates of Rag1−/−Cblb−/− mice. At the molecular level, ST2 undergoes ubiquitination and proteasome-mediated degradation upon IL-33 stimulation, which is abrogated in cells expressing Cbl-b C373A mutant. Therefore, our data indicate that Cbl-b inhibits the development of ILC2 and ILC2-mediated airway inflammation by targeting ST2 for ubiquitination. Supported by NIH R01 AI090901, AI121196, and AI123253
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Kurokawa, Masatsugu, Satoshi Matsukura, Mio Kawaguchi, Koushi Ieki, Shintaro Suzuki, Miho Odaka, Shin Watanabe, et al. "Expression and Effects of IL-33 and ST2 in Allergic Bronchial Asthma: IL-33 Induces Eotaxin Production in Lung Fibroblasts." International Archives of Allergy and Immunology 155, s1 (2011): 12–20. http://dx.doi.org/10.1159/000327259.
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Kharwadkar, Rakshin P., Benjamin J. Ulrich, Yongyao Fu, Byunghee Koh, Andrew Scott Nelson, and Mark H. Kaplan. "A single cell approach to identify the role of IL-9 secreting tissue-resident CD4+ T cells in allergic airway recall responses." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 65.7. http://dx.doi.org/10.4049/jimmunol.204.supp.65.7.
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Abstract Allergic asthma is a chronic intermittent inflammatory lung disease where patients experience relatively few symptoms between exacerbations precipitated by allergen-challenge of allergic memory responses. Allergen-specific CD4+ T cells are believed to be a major mediator of allergic memory responses through the production of type 2 cytokines including IL-4, IL-5, IL-13 and IL-9. Recently, tissue-resident memory (Trm) cells have been identified in peripheral tissues that mediate mucosal barrier immunity. However, the precise role of Trm CD4+ T cells in allergic exacerbations is not clearly defined. In studies to examine the role of IL-9 in allergen-specific Trm responses to Aspergillus fumigatus we observed that all IL-9-secreting T cells had a resident memory phenotype. Inhibition of circulating T cells by administering FTY720 in the last month of rest, diminished the total CD4 T cells population in the lung, while the Th9 cells remained stable. Blockade of IL-9 prior to recall challenge phase reduced overall allergic lung inflammation as assessed both by flow cytometry and single cell RNA-seq. Within eight hours after challenge, IL-9 is one of the top genes identified by scRNA-seq that distinguishes ST2+ and ST2− CD4+ T cell populations in the lung. Using IL-9-reporter mice we also compared gene expression in isolated IL-9+ T cells and other type 2 T cells. These findings demonstrate that IL-9-producing Trms play an important role in mediating allergic memory responses. IL-9 could be a promising therapeutic target specifically in patients showing symptoms of intermittent allergic response.
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Cayrol, Corinne. "IL-33, an Alarmin of the IL-1 Family Involved in Allergic and Non Allergic Inflammation: Focus on the Mechanisms of Regulation of Its Activity." Cells 11, no. 1 (December 30, 2021): 107. http://dx.doi.org/10.3390/cells11010107.
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Interleukin-33 (IL-33) is a member of the interleukin-1 (IL-1) family that is expressed in the nuclei of endothelial and epithelial cells of barrier tissues, among others. It functions as an alarm signal that is released upon tissue or cellular injury. IL-33 plays a central role in the initiation and amplification of type 2 innate immune responses and allergic inflammation by activating various target cells expressing its ST2 receptor, including mast cells and type 2 innate lymphoid cells. Depending on the tissue environment, IL-33 plays a wide variety of roles in parasitic and viral host defense, tissue repair and homeostasis. IL-33 has evolved a variety of sophisticated regulatory mechanisms to control its activity, including nuclear sequestration and proteolytic processing. It is involved in many diseases, including allergic, inflammatory and infectious diseases, and is a promising therapeutic target for the treatment of severe asthma. In this review, I will summarize the literature around this fascinating pleiotropic cytokine. In the first part, I will describe the basics of IL-33, from the discovery of interleukin-33 to its function, including its expression, release and signaling pathway. The second part will be devoted to the regulation of IL-33 protein leading to its activation or inactivation.
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Bie, Qingli, Pan Zhang, Zhaoliang Su, Dong Zheng, Xinyu Ying, Yumin Wu, Huijian Yang, Deyu Chen, Shengjun Wang, and Huaxi Xu. "Polarization of ILC2s in Peripheral Blood Might Contribute to Immunosuppressive Microenvironment in Patients with Gastric Cancer." Journal of Immunology Research 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/923135.
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Newly identified nuocytes or group 2 innate lymphoid cells (ILC2s) play an important role in Th2 cell mediated immunity such as protective immune responses to helminth parasites, allergic asthma, and chronic rhinosinusitis. However, the contributions of ILC2s in the occurrence and development of cancer remain unknown. Our previous study found that there was a predominant Th2 phenotype in patients with gastric cancer. In this study, the ILC2s related genes or molecules in PBMC from patients with gastric cancer were measured, and the potential correlation between them was analyzed. The expression levels of RORα, GATA3, T1/ST2, IL-17RB, CRTH2, IL-33, IL-5, and IL-4 mRNA were significantly increased in patients, but no significant changes were found in ICOS, CD45, and IL-13 expression, and there was a positive correlation between RORαor IL-13 and other related factors, such as ICOS and CD45. The increased frequency of ILC2s was also found in PBMC of patients by flow cytometry. In addition, the mRNA of Arg1 and iNOS were also significantly increased in patients. These results suggested that there are polarized ILC2s in gastric cancer patients which might contribute to immunosuppressive microenvironment and closely related to the upregulation of MDSCs and M2 macrophages.
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Huang, Feng, Xiaoyun Tong, Chunyan Hu, Qiushi Zhang, Yijie Wei, Min Hu, Lingqi Kong, et al. "CAVO Inhibits Airway Inflammation and ILC2s in OVA-Induced Murine Asthma Mice." BioMed Research International 2023 (January 10, 2023): 1–11. http://dx.doi.org/10.1155/2023/8783078.
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Cang-ai volatile oil (CAVO) is an aromatic Chinese medicine and is widely used to treat upper respiratory tract infections in children. However, the mechanism of CAVO in asthma treatment is unclear. In this study, we investigated the effects of CAVO on airway inflammation and the mechanism of inhibiting Group-2 innate lymphoid cells (ILC2s) in asthmatic mice, which was induced with Ovalbumin (OVA). CAVO improved AHR and airway inflammation in asthmatic mice. CAVO reduced the production of interleukin (IL)-2, IL-4, IL-5, IL-6, IL-7, IL-9, IL-13, IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) in the bronchoalveolar lavage fluid (BALF), while increased the production of IL-10, significantly. CAVO also inhibited the suppressor of tumorigenicity 2 (ST2) and IL-33 expressions in the lung tissue. Moreover, flow analyses demonstrated that CAVO inhibited ILC2s activation by reducing the sedimentation of its upstream cytokines, thus alleviating downstream cytokines. This could be because of the downregulated microRNA-155 and upregulated microRNA-146a. CAVO inhibits ILC2s activation, thus further attenuating airway inflammation and AHR in asthmatic mice. These effects may be related to the downregulation of microRNA-155 and upregulation of microRNA-146a.
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Jing, Xiuli, Meixiang Wang, Qiannan Zhuang, Bin Zhao, Jianguo Liu, Shuying Yi, Wengang Song, and Hua Tang. "The formation of memory-like innate lymphoid cells 2 in allergic asthma." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 194.17. http://dx.doi.org/10.4049/jimmunol.198.supp.194.17.
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Abstract Numerous studies have been suggested that ILC2s play a critical role in the initiation of allergic asthmatic airway inflammation, but their property and role in chronic allergic lung inflammation has not been well established. Our study found that purified allergen-experienced ILC2s produce more cytokines than naive ILC2s when stimulated by suboptimal amounts of IL-33 and IL-2 in vitro. Furthermore, upon allergen intranasal re-challenge, allergen-experienced ILC2s proliferate more vigorously and produce much greater amounts of type 2 cytokines than naive ILC2s. These results suggested that allergen-experienced ILC2s showed some memory-like properties in allergic asthma. To further characterize these memory-like ILC2s, we analyzed the expression of some activation surface markers, such as KLRG1, CD62L, CD69, ST2, ICOS, NKG2D, CD44, CD25 and CD122 on ILC2s in the lungs of naive and IL-33-treated mice at different time point. The results showed that during the initial expansion phase, IL-33 treatment resulted in a rapid increase in the number of CD25− ILC2s cells, which peaked at d6. And then the CD25− ILC2 population in the lung started to contract, the number of CD25− ILC2s cells was rapidly declined at d14, a time point that the numbers of CD25+ ILC2s reached their peak. Both of CD25− and CD25+ ILC2s rapidly declined at d30, however, the numbers of CD25+ ILC2s was much higher than CD25− ILC2. Thus, these results suggested that allergen-experienced ILC2s could differentiate into two different memory potential ILC2 subsets, namely CD25− short-term surviving effector ILC2s cells an CD25+ long-term surviving memory ILC2s cells. This work was supported by grants (2015CB943203, 31300730, 81272315, 2016GCC09)
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Cottey, L., N. Jayasekera, H. M. Haitchi, B. Green, C. Grainge, and P. Howarth. "S42 Airway epithelial toll receptor expression in asthma and its relationship to disease severity." Thorax 65, Suppl 4 (November 16, 2010): A21—A22. http://dx.doi.org/10.1136/thx.2010.150912.42.
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Zhang, Zhiyuan, Zhuang Ma, Wenwu Sun, Debin Ma, and Jianping Cao. "The effect of exposure of SO2 in high concentrations on CD19+ cells in reactive airway dysfunction syndrome in rat." European Journal of Inflammation 16 (January 1, 2018): 205873921879190. http://dx.doi.org/10.1177/2058739218791905.
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Reactive airway dysfunction syndrome (RADS) has a clinical manifestation similar to asthma, but some features are different between both the diseases. To probe the effect of CD19+ cells in RADS pathogenesis by inhalation of sulfur dioxide (SO2), rats were exposed to SO2 at 600 ppm for 2 h per day for 7 days and the CD19 expression in lung tissue was detected both at mRNA and protein levels by RT-PCR and western blot. The percentages of CD19+ and CD19+ CD23+ cells were measured by flow cytometry. IgG, IgA, and IgE in serum and bronchoalveolar lavage fluid (BALF) were detected by enzyme-linked immunosorbent assay (ELISA). Histological analysis was performed. The results showed that expression of CD19 in SO2 exposure group was lower than that in the control both at mRNA and protein levels ( P < 0.05). Flow cytometry analysis showed that the percentages of CD19+ and CD19+ CD23+ were significantly lower in the SO2 exposed group than that in the control ( P < 0.05). There was no difference between the control and SO2 exposed groups in both serum and BALF levels of IgG, IgA, and IgE. Pathological changes, such as chronic bronchitis, local alveolar hemorrhage, and lymphocytes infiltration were observed in SO2 exposed. RADS is a non-immunogenicity, chronic airway inflammatory disease caused by irritation of harmful factor and manifests as airway hyperresposiveness.
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Contreras, Amanda, Darin L. Wiesner, Brock Kingstad-Bakke, Woojong Lee, John P. Svaren, Bruce S. Klein, and M. Suresh. "BACH2 in TRegs Limits the Number of Adipose Tissue Regulatory T Cells and Restrains Type 2 Immunity to Fungal Allergens." Journal of Immunology Research 2022 (August 5, 2022): 1–19. http://dx.doi.org/10.1155/2022/6789055.
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FoxP3+ regulatory T cells (Tregs) are essential for self-tolerance and moderating tissue-damaging inflammation. Tregs that develop and mature in the thymus are classified as central Tregs or effector Tregs based on whether Tregs predominately inhabit secondary lymphoid organs (central Tregs) or tissues (effector Tregs). By generating mice that are conditionally deficient for Bach2 in peripheral Tregs, we have examined the role of Bach2 in regulating Treg homeostasis and effector functions. Unlike global and T cell-specific Bach2-deficient mice, Treg-specific Bach2 ablation did not result in unprovoked TH2 inflammation in the lungs. However, Bach2 deficiency in Tregs led to augmented expressions of IRF4, BATF, and GATA3 and a significant increase in the accumulation of ST2 (IL-33R)+ve effector Tregs in the spleen and visceral adipose tissue (VAT) but not in the lungs. Enhanced Bach2-deficient Treg numbers in VAT was not linked to hyperresponsiveness to exogenous IL-33 in vivo. Most strikingly, Treg-specific Bach2 deficiency resulted in enhanced fungal protease-induced Type 2 allergic inflammation in the lungs, with no detectable effects on Type 1 responses to systemic or respiratory viral infections. In summary, we ascribe vital roles for Bach2 in peripheral Tregs: as a transcriptional checkpoint to limit precocious differentiation into effector Tregs in lymphoid tissues and as a regulator of the functional program that restrains Type 2 but not Type 1 inflammation in lungs. Results presented in this manuscript implicate dysregulated Tregs in the pathogenesis of airway hypersensitivities, asthma, and other allergic disorders.
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LI, Li, Lingfei KONG, Xiubin FANG, Changlin JIANG, Yating WANG, Zhaoshuang ZHONG, Qiyu SUN, et al. "SH2-Bβ expression in alveolar macrophages in BAL fluid of asthmatic guinea pigs and its role in NGF-TrkA-mediated asthma." Respirology 14, no. 1 (January 2009): 60–68. http://dx.doi.org/10.1111/j.1440-1843.2008.01417.x.
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Karaesmen, Ezgi, Theresa E. Hahn, Alexander Dile, Abbas Rizvi, Junke Wang, Tao Wang, Michael D. Haagenson, et al. "Multiple Functional Donor Polymorphisms in IL1RL1 region Associate with Death Due to GvHD or Infection after Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation (HCT) for AML and MDS." Blood 132, Supplement 1 (November 29, 2018): 312. http://dx.doi.org/10.1182/blood-2018-99-115276.
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Abstract The last two authors contributed equally Elevated soluble Stimulation-2 (sST2), the decoy IL-33 receptor, in plasma/serum post-HSCT is a biomarker for death due to GvHD. ST2 is the product of IL1RL1 (2q12.1) and this ~.5Mb region contains >300 single nucleotide polymorphisms (SNPs) significantly associated (P<5x10-8) with plasma levels of sST2 in healthy participants from the Framingham Heart Study (FHS). Many of these SNPs are genome-wide associated with infection-related phenotypes, including asthma, Crohn's disease, ulcerative colitis and celiac disease. Given these relationships, we analyzed the association of ST2 SNPs with death due to GvHD or infection within one year after HLA-matched unrelated donor HCT for AML or MDS to identify functional SNPs that could potentially aid in donor selection. We measured plasma/serum sST2 levels in pre-HCT samples in a subset of AML and MDS patients (n=759) and their donors (n=757) from DISCOVeRY-BMT, a GWAS of >3,000 recipient-unrelated donor pairs reported to the CIBMTR between 2000-2011. After quality control (info>.8, MAF>.005), 3613 SNPs in the IL1RL1 region were tested for association with sST2 levels; 1541 donor SNPs associated with sST2 levels (P<.05), which validated 99% of the FHS sST2 SNP associations. To assess the contribution of these donor variants to post-HCT survival, we constructed competing risk models with clinical variables using stepwise Akaike Information Criterion (AIC), then tested each of the 1541 donor SNPs for association with each outcome in the two DISCOVeRY-BMT cohorts. Causes of death were previously adjudicated by a multi-member panel. Meta-analyses of the two cohorts identified 13 GvHD-death associated SNPs and 118 infection-death associated SNPs. Sensitivity analyses show 91/118 SNPs are still significant after excluding patients with a history of acute GvHD grade III-IV (Figure 1). When taking correlations into account, we found 10 and three independent SNPs (R2<.6) associate with death due to infection and GvHD, respectively. There were no overlapping SNP associations between GvHD-death or infection-death (Figure 1). For GvHD-death associated SNPs, alleles associated with higher sST2 levels associate with increased risk for GvHD-death, while for infection-death SNPs, alleles associated with higher sST2 levels reduced risk of infection-death. AIC multivariable models for GvHD-death included AML diagnosis, recipient obesity (>30 mg/kg2), peripheral blood cell source, donor age, rs1558645 (Pmeta=.001), and rs2310241(Pmeta=.0003), for which the risk alleles at each SNP increased risk of GvHD death ~1.5 fold. The model for infection-death included advanced disease at HCT, recipient/donor CMV status, peripheral blood cell source, rs13019803 (Pmeta=1.1 x 10-6), rs13015714 (Pmeta=5 x 10-4) and rs4851601 (Pmeta=2 x 10-6), with risk alleles at each SNP increasing risk of infection-death ~2-fold. To capture the total contribution of these donor variants to each outcome we created multi-allele models for GvHD-death (0-4 alleles) and infection-death (0-6 alleles).The multi-allele GvHD models showed a 1.5 fold increased risk of GvHD-death with each additional allele (Pmeta=3.4 x 10-6 ) (Figure 2). Individuals whose donors are homozygous for both risk alleles at each SNP have a ~3 fold, and ~2 fold higher risk of dying of GvHD versus those with zero, and 1-2 risk allele(s), respectively. The multi-allele infection models (0-6 alleles) show a ~2 fold increased risk of infection-death (Pmeta= 1.22 x 10-10) with each risk allele (Figure 2). sST2 is one of the most reproducible GvHD biomarkers to date. As hypothesized, specific alleles correlated with high sST2 levels in donors and with GvHD-death. Our novel finding is that some ST2 alleles associated with low sST2 levels correlated with infection-death. These results are not without precedent, for example the low-sST2 associated allele in rs13019803 (T) associates with higher mortality in the CHARGE consortium. The risk allele in rs13015714 (T) is significantly associated with lower IL1RL1 and IL18R1 (P= 5 x 10-10) gene expression in lung tissue, indicating biochemical functions for these SNPs. Importantly the non-risk allele in all 5 variants are common (>20%) across races and ethnicities, which means there is an opportunity to select donors without combinations of these variants and perhaps without the requirement of measuring the protein level pre-transplant. Disclosures McCarthy: Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Lee:Kadmon: Research Funding; Amgen: Consultancy, Research Funding; Mallinckrodt: Honoraria; Incyte: Consultancy; Pfizer: Consultancy; Onyx: Research Funding; Takeda: Research Funding. Paczesny:Viracor IBT Laboratories: Patents & Royalties.
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Zoltowska Nilsson, A. M., Y. Lei, M. Adner, and G. P. Nilsson. "Mast cell-dependent IL-33/ST2 signaling is protective against the development of airway hyperresponsiveness in a house dust mite mouse model of asthma." American Journal of Physiology-Lung Cellular and Molecular Physiology 314, no. 3 (March 1, 2018): L484—L492. http://dx.doi.org/10.1152/ajplung.00270.2017.
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Interleukin-33 (IL-33) and its receptor ST2 have been influentially associated with the pathophysiology of asthma. Due to the divergent roles of IL-33 in regulating mast cell functions, there is a need to further characterize IL-33/ST2-dependent mast cell responses and their significance in the context of asthma. This study aimed to investigate how IL-33/ST2-dependent mast cell responses contribute to the development of airway hyperresponsiveness (AHR) and airway inflammation in a mouse model of house dust mite (HDM)-induced asthma. Mast cell-deficient C57BL/6-KitW-sh (Wsh) mice engrafted with either wild-type (Wsh + MC-WT) or ST2-deficient bone marrow-derived mast cells (Wsh + MC-ST2KO) were exposed to HDM delivered intranasally. An exacerbated development of AHR in response to HDM was seen in Wsh + MC-ST2KO compared with Wsh + MC-WT mice. The contribution of this IL-33/ST2-dependent mast cell response to AHR seems to reside within the smaller airways in the peripheral parts of the lung, as suggested by the isolated yet marked effect on tissue resistance. Considering the absence of a parallel increase in cellular inflammation in bronchoalveolar lavage fluid (BALF) and lung, the aggravated AHR in Wsh + MC-ST2KO mice seems to be independent of cellular inflammation. We observed an association between the elevated AHR and reduced PGE2 levels in BALF. Due to the protective properties of PGE2 in airway responses, it is conceivable that IL-33/ST2-dependent mast cell induction of PGE2 could be responsible for the dampening effect on AHR. In conclusion, we reveal that IL-33/ST2-dependent mast cell responses can have a protective, rather than causative role, in the development of AHR.
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Zhang, Liwen, Yu Wan, Liang Ma, Kaihong Xu, and Baojin Cheng. "Inhibition of NF-κB/IL-33/ST2 Axis Ameliorates Acute Bronchiolitis Induced by Respiratory Syncytial Virus." Journal of Immunology Research 2021 (August 4, 2021): 1–11. http://dx.doi.org/10.1155/2021/6625551.
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Background/Aim. Bronchiolitis is a common acute lower respiratory tract infectious disease in infants. Respiratory syncytial virus (RSV) infection is one of the main causes. Bronchiolitis can lead to a significant increase in the incidence of asthma in young children, but the mechanism of bronchiolitis transforming into asthma is still unclear. The study was aimed at investigating the role of NF-κB/IL-33/ST2 axis on RSV-induced acute bronchiolitis. Methods. A total of 40 infants diagnosed with acute bronchiolitis infected by RSV, and 20 normal infants were included in this study. BALB/c mice (6-8 weeks old, 20 ± 1.1 g) were used as study models. Enzyme-linked immunosorbent assay (ELISA), quantitative real time PCR, western blot analysis, immunohistochemical staining, and flow cytometry analysis were performed to examine relevant indicators. Results. IL-33 level was significantly elevated, and Th1/Th2 ratio is imbalance after in infants with acute bronchiolitis. In vivo study, we found that NF-κB/IL-33/ST2 axis is mediated the Th2 cytokine levels and BAL cell number induced by RSV. Acute bronchiolitis induced by RSV in a mouse model is attenuated after inhibition of NF-κB/IL-33/ST2 pathway. Moreover, we also confirmed that macrophages are important sources of IL-33 and are regulated by NF-κB pathway in RSV-induced mice. Conclusion. We confirmed that inhibition of NF-κB/IL-33/ST2 axis could attenuate acute bronchiolitis by RSV infected. Our findings not only demonstrate the potential role of IL-33 antibody in attenuating RSV-induced lung damage but also provide a new insight into better prevention of RSV-induced asthma by mediating NF-κB/IL-33/ST2 axis.
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Dong, Yonghua, Hua Hu, Dandan Fu, Shuting Zheng, Qingqing Wang, Keshav K C, Xiangfeng Song, and Zhongwei Tian. "Serum Expression of IL-33 and ST2 in Patients with Psoriasis Vulgaris." Archives of Iranian Medicine 24, no. 9 (September 1, 2021): 689–95. http://dx.doi.org/10.34172/aim.2021.99.
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Background: Psoriasis vulgaris (PsV) is an immune-mediated skin disease of unknown mechanism. Interleukin 33 (IL-33) is a member of IL-1 cytokine family and suppression of tumorigenicity 2 (ST2) is the specific ligand of IL-33. It has been found that IL-33 and ST2 are increased in psoriatic lesions, but the expression levels in serum and their relationship to clinical features are still unclear. The aim of this study is to assess IL-33, ST2, IL-17 and IL-5 serum levels as well as serum concentration of blood glucose and blood lipids in PsV patients and their relationship with clinical characteristics. Methods: Sixty-eight PsV samples and 60 healthy individuals were recruited. Serum levels of IL-33, ST2, IL-17 and IL-5 were measured by enzyme-linked immunosorbent assay and blood glucose and blood lipid were assayed by automatic biochemical analyzer. Results: Serum levels of IL-33, ST2, IL-17 and IL-5 were increased significantly in PsV patients compared with controls (P<0.01). Cytokines were overexpressed in PsV patients during active stages compared with controls (P<0.05). Expression levels of IL-33, ST2 and IL-17 confirmed a significance in different severity groups of PsV patients (P<0.05). Serum concentration of triglyceride (TG) was also increased compared with controls (P=0.024). IL-33 levels were positively correlated with total cholesterol (TC) levels (r=0.319, P=0.008). Conclusion: IL-33/ST2 could generally reflect the activity and disease severity in PsV patients, which indicates that the IL-33/ST2 signaling pathway plays an important role in the pathogenesis of PsV.
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Townsend, Michael J., Padraic G. Fallon, David J. Matthews, Helen E. Jolin, and Andrew N. J. McKenzie. "T1/St2-Deficient Mice Demonstrate the Importance of T1/St2 in Developing Primary T Helper Cell Type 2 Responses." Journal of Experimental Medicine 191, no. 6 (March 20, 2000): 1069–76. http://dx.doi.org/10.1084/jem.191.6.1069.
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We have generated mice with a deficiency in T1/ST2 expression to clarify the roles of T1/ST2 in T helper cell type 2 (Th2) responses. Using immunological challenges normally characterized by a Th2-like response, we have compared the responses of T1/ST2-deficient mice with those generated by wild-type mice. Using a primary pulmonary granuloma model, induced with Schistosoma mansoni eggs, we demonstrate that granuloma formation, characterized by eosinophil infiltration, is abrogated in T1/ST2-deficient mice. Furthermore, we clearly demonstrate that in the absence of T1/ST2 expression, the levels of Th2 cytokine production are severely impaired after immunization. Thus, in a secondary pulmonary granuloma model, draining lymph node cells from the T1/ST2-deficient animals produced significantly reduced levels of IL-4 and IL-5, despite developing granulomas of a magnitude similar to those of wild-type mice and comparable antigen-specific immunoglobulin isotype production. These data clearly demonstrate that T1/ST2 expression plays a role in the development of Th2-like cytokine responses and indicate that effector functions are inhibited in its absence.
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Baumann, Claudia, Weldy V. Bonilla, Anja Fröhlich, Caroline Helmstetter, Michael Peine, Ahmed N. Hegazy, Daniel D. Pinschewer, and Max Löhning. "T-bet– and STAT4–dependent IL-33 receptor expression directly promotes antiviral Th1 cell responses." Proceedings of the National Academy of Sciences 112, no. 13 (March 17, 2015): 4056–61. http://dx.doi.org/10.1073/pnas.1418549112.
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During infection, the release of damage-associated molecular patterns, so-called “alarmins,” orchestrates the immune response. The alarmin IL-33 plays a role in a wide range of pathologies. Upon release, IL-33 signals through its receptor ST2, which reportedly is expressed only on CD4+ T cells of the Th2 and regulatory subsets. Here we show that Th1 effector cells also express ST2 upon differentiation in vitro and in vivo during lymphocytic choriomeningitis virus (LCMV) infection. The expression of ST2 on Th1 cells was transient, in contrast to constitutive ST2 expression on Th2 cells, and marked highly activated effector cells. ST2 expression on virus-specific Th1 cells depended on the Th1-associated transcription factors T-bet and STAT4. ST2 deficiency resulted in a T-cell–intrinsic impairment of LCMV-specific Th1 effector responses in both mixed bone marrow-chimeric mice and adoptive cell transfer experiments. ST2-deficient virus-specific CD4+ T cells showed impaired expansion, Th1 effector differentiation, and antiviral cytokine production. Consequently, these cells mediated little virus-induced immunopathology. Thus, IL-33 acts as a critical and direct cofactor to drive antiviral Th1 effector cell activation, with implications for vaccination strategies and immunotherapeutic approaches.
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Bloodworth, Melissa H., Mark Rusznak, Lisa Bastarache, Janey Wang, Joshua C. Denny, and R. Stokes Peebles. "Association of ST2 polymorphisms with atopy, asthma, and leukemia." Journal of Allergy and Clinical Immunology 142, no. 3 (September 2018): 991–93. http://dx.doi.org/10.1016/j.jaci.2018.03.020.
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Brandt, Eric B., Paige E. Bolcas, Brandy P. Ruff, and Gurjit K. Khurana Hershey. "IL33 signaling contributes to diesel exhaust particles-induced asthma exacerbations by promoting innate and adaptive type 2 and type 17 responses." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 44.20. http://dx.doi.org/10.4049/jimmunol.200.supp.44.20.
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Abstract Rationale Exposure to traffic pollution, notably diesel exhaust particles (DEP), promote asthma exacerbations and a mixed Th2/Th17 response. The contribution of TSLP and IL33, generated by sressed lung epithelial cells, to DEP-induced asthma exacerbations remains poorly understood. Method We used TSLP receptor deficient mice, mice lacking the IL33 receptor (ST2) and Balb/c control mice and exposed them 9 times over a 3-week period to saline, house dust mite extract (HDM; 10ug) and/or DEP (100ug). Seven weeks later some mice received a single HDM challenge to assess memory responses. Airway hyper-responsiveness (AHR), BALF inflammation and lung T-cells and ILC subsets were assessed after primary and recall responses. Results DEP co-exposure with HDM exacerbates HDM-induced AHR and Th2 responses. AHR was similar between TSLPR deficient mice and control mice exposed to HDM+DEP. In contrast, AHR was significantly decreased in ST2-deficient mice compared to wild type mice. The impact of ST2 deficiency on lung accumulation of ILC2 and Th2 cells was modest. Following HDM+DEP co-exposures, decreases in ILC3, γδ T-cells and Th17 cells were observed in the lungs of ST2 deficient mice compared to control mice. The in vivo HDM recall response recapitulated the impaired AHR associated with decreases in IL17A secreting cells observed after the primary response in HDM+DEP exposed ST2 deficient mice. Finally, a decrease in lung levels of pathogenic IL5/IL13/IL17A producing CD4+ T-cells was observed after the primary and recall responses. Conclusions IL33 but not TSLP contributes to DEP-induced asthma exacerbations by affecting the accumulation of innate and adaptive type 2 and type 17 cells, notably pathogenic Th2/Th17 cells.
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Valeff, Natalin Jimena, Maria Silvia Ventimiglia, Florencia Quadrana, and Federico Jensen. "ST2-expressing B1 B cells acquire an anti-inflammatory capacity during pregnancy in mice." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 235.14. http://dx.doi.org/10.4049/jimmunol.204.supp.235.14.
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Abstract In the context of pregnancy, it is known that IL-33 induces the production of anti-inflammatory molecules by decidual B1 cells, protecting against preterm birth (PTB) in human and mouse. We have previously showed that expression of IL-33 receptor, Il1rl1 (ST2) is significantly upregulated in splenic B cells during mid pregnancy, predominantly in B1 cell subset. Furthermore, using an LPS induced PTB mouse model, we observed increased numbers of splenic and decidual ST2-expressing B1 cells in the acute phase of PTB as compared to term pregnant females. We aimed to investigate here the anti-inflammatory properties of ST2-expressing B1 cells during pregnancy. Total splenocytes from pregnant (P) and non-pregnant (NP) mice were isolated and cultured for 24h with/without LPS (10 μgr/ml), ST2 expression and cytokine production by ST2+ B1 cells was evaluated by flow cytometry. B1 cells from P mice stimulated with LPS showed significantly higher levels of ST2 expression. ST2+ B1 cells produced significantly higher levels of IL-10 and significantly lower levels of TNF-α and IL-17 as compared to ST2+ B1 cells from NP mice. In a separate project in our laboratory we demonstrated that prophylactic treatment with probiotic Lactobacillus kefiri prevented LPS-induced PTB in mice. Interestingly, we observed that numbers of splenic and decidual ST2-expressing B1 cells were increased in L. kefiri treated mice that were protected against LPS-induced PTB. Our data strongly suggest an anti-inflammatory capacity of ST2-expressing B1 cells during gestation, presumably to ensure pregnancy wellbeing and prevent inflammation induced PTB.
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Manetti, Mirko, Lidia Ibba-Manneschi, Vasiliki Liakouli, Serena Guiducci, Anna Franca Milia, Gemma Benelli, Alessandra Marrelli, et al. "The IL1-like cytokine IL33 and its receptor ST2 are abnormally expressed in the affected skin and visceral organs of patients with systemic sclerosis." Annals of the Rheumatic Diseases 69, no. 3 (September 23, 2009): 598–605. http://dx.doi.org/10.1136/ard.2009.119321.
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BackgroundEarly endothelial cell (EC) activation/damage and profibrotic Th2-associated cytokines play a pivotal role in systemic sclerosis (SSc). Interleukin 33 (IL33) is a novel member of the IL1 family that promotes Th2 responses and inflammation through the ST2 receptor. IL33 is also a chromatin-associated transcriptional regulator in ECs.ObjectiveTo investigate the role of the IL33/ST2 axis in SSc.MethodsSkin biopsies were obtained from 30 patients with SSc (15 early/15 late stage) and 10 healthy subjects. Lung, kidney, heart, oesophagus, stomach, placenta biopsies and bronchoalveolar lavage cells from patients with SSc and controls were also analysed. IL33/ST2 expression was investigated by immunohistology, confocal immunofluorescence microscopy, western blotting and RT-PCR.ResultsIn skin biopsies from control subjects, constitutive nuclear IL33 protein expression was found in dermal ECs and keratinocytes, while ST2 was weakly expressed in ECs and fibroblasts. In skin biopsies from patients with early SSc, IL33 protein was downregulated or absent in ECs and epidermis while IL33 mRNA was normally expressed or even upregulated. Moreover, ECs, perivascular infiltrating mast cells, CD68-positive macrophages, CD3-positive T cells, CD20-positive B cells and activated fibroblasts/myofibroblasts exhibited strong ST2 expression. In skin biopsies from patients with late SSc, IL33 was constitutively found in most ECs while ST2 immunostaining was weaker. In early SSc, the loss of endothelial IL33 protein and the overexpression of ST2 involved all affected organs. Dermal and pulmonary fibroblasts showed IL33 expression in SSc.ConclusionIL33 and ST2 are abnormally expressed in SSc. In early SSc, upon EC activation/damage IL33 may be mobilised from ECs to signal through ST2 in key profibrotic players such as inflammatory/immune cells and fibroblasts/myofibroblasts.
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Lee, Jyh-Hong, Li-Chieh Wang, Hsin-Hui Yu, Yu-Tsan Lin, Yao-Hsu Yang, and Bor-Luen Chiang. "Type I IL-1 Receptor (IL-1RI) as Potential New Therapeutic Target for Bronchial Asthma." Mediators of Inflammation 2010 (2010): 1–7. http://dx.doi.org/10.1155/2010/567351.
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The IL-1R/TLR family has been receiving considerable attention as potential regulators of inflammation through their ability to act as either activators or suppressors of inflammation. Asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness, allergic inflammation, elevated serum total, allergen-specific IgE levels, and increased Th2 cytokine production. The discovery that the IL-1RI–IL-1 and ST2–IL-33 pathways are crucial for allergic inflammation has raised interest in these receptors as potential targets for developing new therapeutic strategies for bronchial asthma. This paper discusses the current use of neutralizing mAb or soluble receptor constructs to deplete cytokines, the use of neutralizing mAb or recombinant receptor antagonists to block cytokine receptors, and gene therapy from experimental studies in asthma. Targeting IL-1RI–IL-1 as well as ST2–IL-33 pathways may promise a disease-modifying approach in the future.
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Reichenbach, Dawn K., Vincent Schwarze, Benjamin M. Matta, Victor Tkachev, Elisabeth Lieberknecht, Quan Liu, Brent H. Koehn, et al. "The IL-33/ST2 axis augments effector T-cell responses during acute GVHD." Blood 125, no. 20 (May 14, 2015): 3183–92. http://dx.doi.org/10.1182/blood-2014-10-606830.
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Key Points IL-33 and ST2 expression are increased post-conditioning and with GVHD, resulting in increased T-cell activation via the IL-33/ST2 axis. Infusion of ST2-Fc protein exploits sST2’s function as a negative regulator of acute GVHD inhibiting pro-inflammatory cytokines.
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Obata-Ninomiya, Kazushige, Kenji Ishiwata, Hisanobu Nakano, Yusuke Endo, Tomomi Ichikawa, Atsushi Onodera, Kiyoshi Hirahara, Yoshitaka Okamoto, Hirotaka Kanuka, and Toshinori Nakayama. "CXCR6+ST2+ memory T helper 2 cells induced the expression of major basic protein in eosinophils to reduce the fecundity of helminth." Proceedings of the National Academy of Sciences 115, no. 42 (October 1, 2018): E9849—E9858. http://dx.doi.org/10.1073/pnas.1714731115.
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Memory T helper (mTh) cells play important roles in the reinfection of pathogens and drive the pathogenesis of diseases. While recent studies have characterized the pathogenic mTh2 cell subpopulations driving allergic inflammation, those that induce immune responses against helminth infection remain unknown. We found that IL-5–producing CXCR6+ST2+CD44+ mTh2 cells play a crucial role in the IL-33–dependent inhibition of the fecundity of helminth, whereas other ST2− mTh2 cells do not. Although both cell types induced the infiltration of granulocytes, especially eosinophils, into the lungs in response to helminth infection, the ST2+ mTh2 cell-induced eosinophils expressed higher levels of major basic protein (MBP), which is important for reducing the fecundity of Nippostrongylus brasiliensis (Nb), than ST2− mTh2 cell-induced ones. Notably, we also found that ST2+ Treg cells but not ST2− Treg cells suppressed CXCR6+ST2+ mTh2 cell-mediated immune responses. Taken together, these findings show that we identified a mechanism against helminth elicited by a subpopulation of IL-5–producing mTh2 cells through the accumulation of eosinophils strongly expressing MBP in the lungs.
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Begum, Salma, Barry E. Perlman, Nuriban Valero-Pacheco, Valerie O’Besso, Tracy Wu, Sara S. Morelli, Aimee M. Beaulieu, and Nataki C. Douglas. "Dynamic Expression of Interleukin-33 and ST2 in the Mouse Reproductive Tract Is Influenced by Superovulation." Journal of Histochemistry & Cytochemistry 68, no. 4 (February 28, 2020): 253–67. http://dx.doi.org/10.1369/0022155420911049.
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Interleukin-33 (IL-33) is an IL-1 family cytokine with pleiotropic effects on diverse cell types. Dysregulated IL-33 signaling has been implicated in pregnancy-related disorders, including preeclampsia and recurrent pregnancy loss, and in ovarian function in women undergoing controlled ovarian stimulation for in vitro fertilization. To date, expression of IL-33 and its receptor subunit, ST2, in the female reproductive tract remains poorly characterized. We identify IL-33-expressing oocytes surrounded by ST2-expressing granulosa cells at all stages of follicular development, in addition to IL-33+ and ST2+ non-endothelial cells in the ovarian stroma and theca layer in ovaries from adult mice. These expression patterns are similar in estrus- and diestrus-stage adults and in pubescent mice, suggesting a role for IL-33 signaling in ovarian function throughout development and in the estrous cycle. In the uterus, we find expression of IL-33 and ST2 in glandular and luminal epithelia during estrus and at the initiation of pregnancy. Uterine IL-33 expression was modulated by the estrous cycle and was reduced in pubescent females. Last, superovulation increases transcripts for IL-33 and the soluble form of ST2 (sST2) in ovaries, and for IL-33 in uteri. Collectively, our findings lay the foundation for studies identifying cell type-specific requirements for IL-33/ST2 signaling in the establishment and maintenance of mouse pregnancy.
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Otsuka, Eri, Akira Yamaguchi, Shigehisa Hirose, and Hiromi Hagiwara. "Characterization of osteoblastic differentiation of stromal cell line ST2 that is induced by ascorbic acid." American Journal of Physiology-Cell Physiology 277, no. 1 (July 1, 1999): C132—C138. http://dx.doi.org/10.1152/ajpcell.1999.277.1.c132.
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The stromal cell line ST2, derived from mouse bone marrow, differentiated into osteoblast-like cells in response to ascorbic acid. Ascorbic acid induced alkaline phosphatase (ALPase) activity, the expression of mRNAs for proteins that are markers of osteoblastic differentiation, the deposition of calcium, and the formation of mineralized nodules by ST2 cells. We investigated the mechanism whereby ascorbic acid induced the differentiation of ST2 cells. Inhibitors of the formation of collagen triple helices completely blocked the effects of ascorbic acid on ST2 cells, an indication that matrix formation by type I collagen is essential for the induction of osteoblastic differentiation of ST2 cells by ascorbic acid. We furthermore examined the effects of bone morphogenetic proteins (BMPs) on the differentiation of ST2 cells induced by ascorbic acid. Ascorbic acid had no effect on the expression of mRNAs for BMP-4 and the BMP receptors. However, a soluble form of BMP receptor IA inhibited the induction of ALPase activity by ascorbic acid. These results suggest that ascorbic acid might promote the differentiation of ST2 cells into osteoblast-like cells by inducing the formation of a matrix of type I collagen, with subsequent activation of the signaling pathways that involve BMPs.
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Wierzbicka, Justyna M., Anna Piotrowska, Dorota Purzycka-Bohdan, Anna Olszewska, Joanna I. Nowak, Aneta Szczerkowska-Dobosz, Bogusław Nedoszytko, Roman J. Nowicki, and Michał A. Żmijewski. "The Effects of Vitamin D on the Expression of IL-33 and Its Receptor ST2 in Skin Cells; Potential Implication for Psoriasis." International Journal of Molecular Sciences 22, no. 23 (November 29, 2021): 12907. http://dx.doi.org/10.3390/ijms222312907.
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Interleukin 33 (IL-33) belongs to the IL-1 family and is produced constitutively by epithelial and endothelial cells of various organs, such as the skin. It takes part in the maintenance of tissue homeostasis, repair, and immune response, including activation of Th2 lymphocytes. Its involvement in pathogenesis of several inflammatory diseases including psoriasis was also suggested, but this is not fully understood. The aim of the study was to investigate expression of IL-33 and its receptor, ST2, in psoriasis, and the effects of the active form of vitamin D (1,25(OH)2D3) on their expression in skin cells. Here we examined mRNA and protein profiles of IL-33 and ST2 in 18 psoriatic patients and healthy volunteers by qPCR and immunostaining techniques. Potential effects of 1,25(OH)2D3 and its receptor (VDR) on the expression of IL-33 and ST2 were tested in cultured keratinocytes, melanocytes, fibroblasts, and basal cell carcinoma cells. It was shown that 1,25(OH)2D3 effectively stimulated expression of IL-33 and its receptor ST2’s mRNAs in a time-dependent manner, in keratinocytes and to the lesser extends in melanocytes, but not in fibroblasts. Furthermore, the effect of vitamin D on expression of IL-33 and ST2 was VDR-dependent. Finally, we demonstrated that the expression of mRNA for IL-33 was mainly elevated in the psoriatic skin but not in its margin. Interestingly, ST2 mRNA was downregulated in psoriatic lesion compared to both marginal tissue as well as healthy skin. Our data indicated that vitamin D can modulate IL-33 signaling, opening up new perspectives for our understanding of the mechanism of vitamin D action in psoriasis therapy.
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Tonacci, Alessandro, Paolina Quattrocchi, and Sebastiano Gangemi. "IL33/ST2 Axis in Diabetic Kidney Disease: A Literature Review." Medicina 55, no. 2 (February 14, 2019): 50. http://dx.doi.org/10.3390/medicina55020050.
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Interleukin-33 (IL-33) is a cytokine belonging to the IL-1 family, playing a role in inflammatory, infectious and autoimmune diseases and expressed in the cellular nucleus in several tissues. High levels of IL-33 are expressed in epithelial barrier tissues and endothelial barriers. ST2 is a receptor for IL-33, expressed selectively on a subset of Th2 cells, mediating some of their functions. The IL-33/ST2 axis plays an important role in several acute and chronic inflammatory diseases, including asthma and rheumatoid arthritis. Different disorders are related to the activity of IL-33, ST2, or their axis, including cardiovascular disease or renal disturbances. Therefore, in the present work, a literature review was conducted, covering the period from 1 January 2000 to 30 November 2018, in PubMed, ScienceDirect, and Google Scholar database, to assess the involvement of the IL-33/ST2 axis in diabetic kidney disease. 6 articles directly dealing with the argument were identified, highlighting a clear link between IL-33/ST2 axis and diabetic kidney disease or related nephropathy. Overall, the involvement of ST2 seems to be more predictive than IL-33, especially in investigating the deterioration of kidney function; however, both compounds are pivotal in the field of renal diseases. Future studies are required to confirm the scientific evidences on larger and more heterogeneous cohorts.
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Löhning, Max, Jane L. Grogan, Anthony J. Coyle, Maria Yazdanbakhsh, Christian Meisel, Jose-Carlos Gutierrez-Ramos, Andreas Radbruch, and Thomas Kamradt. "T1/ST2 Expression Is Enhanced on CD4+ T Cells from Schistosome Egg-Induced Granulomas: Analysis of Th Cell Cytokine Coexpression Ex Vivo." Journal of Immunology 162, no. 7 (April 1, 1999): 3882–89. http://dx.doi.org/10.4049/jimmunol.162.7.3882.
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Abstract Th cells are categorized into subsets based on the cytokine production of in vitro-differentiated Th populations. For in vivo-differentiated Th subsets, little is known about the heterogeneity of cytokine production in single cells. We recently described a molecule, T1/ST2, that is preferentially expressed on the surface of Th2 cells. Here we combined high-gradient magnetic cell separation with four-color single-cell cytometry to analyze simultaneously three intracellular cytokines and T1/ST2 surface expression on CD4+ cells from lungs containing granulomas induced by Schistosoma mansoni eggs. T1/ST2 was highly up-regulated on CD4+ T cells from hepatic granulomas and granulomatous lungs. T1/ST2+ cells from granulomatous lungs preferentially produced type 2 cytokines ex vivo. In the total CD4+ population, coexpression of type 1 and type 2 cytokines occurred frequently. However, such coproduction was drastically reduced in T1/ST2+ cells compared with T1/ST2− cells. Coexpression of type 1 and type 2 cytokines was also rare in cells simultaneously producing two cytokines of one type. These findings indicate that individual CD4+ T cells in vivo have different levels of commitment to a certain Th phenotype. Coexpression of two type 2 cytokines or production of one type 2 cytokine together with surface expression of T1/ST2 indicate advanced commitment to the Th2 phenotype.
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Rasheed, Kashif, Ugo Moens, Benedetta Policastro, John Inge Johnsen, Virve Koljonen, Harri Sihto, Weng-Onn Lui, and Baldur Sveinbjørnsson. "The Merkel Cell Polyomavirus T-Antigens and IL-33/ST2-IL1RAcP Axis: Possible Role in Merkel Cell Carcinoma." International Journal of Molecular Sciences 23, no. 7 (March 28, 2022): 3702. http://dx.doi.org/10.3390/ijms23073702.
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Merkel cell polyomavirus (MCPyV) is a causal factor in Merkel cell carcinoma (MCC). The oncogenic potential is mediated through its viral oncoproteins large T-antigen (LT) and small T-antigen (sT). Cytokines produced by tumor cells play an important role in cancer pathogenesis, and viruses affect their expression. Therefore, we compared human cytokine and receptor transcript levels in virus positive (V+) and virus negative (V−) MCC cell lines. Increased expression of IL-33, a potent modulator of tumor microenvironment, was observed in V+ MCC cell lines when compared to V− MCC-13 cells. Transient transfection studies with luciferase reporter plasmids demonstrated that LT and sT stimulated IL-33, ST2/IL1RL1 and IL1RAcP promoter activity. The induction of IL-33 expression was confirmed by transfecting MCC-13 cells with MCPyV LT. Furthermore, recombinant human cytokine domain IL-33 induced activation of MAP kinase and NF-κB pathways, which could be blocked by a ST2 receptor antibody. Immunohistochemical analysis demonstrated a significantly stronger IL-33, ST2, and IL1RAcP expression in MCC tissues compared to normal skin. Of interest, significantly higher IL-33 and IL1RAcP protein levels were observed in MCC patient plasma compared to plasma from healthy controls. Previous studies have demonstrated the implication of the IL-33/STL2 pathway in cancer. Because our results revealed a T-antigens-dependent induction of the IL-33/ST2 axis, IL-33/ST2 may play a role in the tumorigenesis of MCPyV-positive MCC. Therefore, neutralizing the IL-33/ST2 axis may present a novel therapeutic approach for MCC patients.
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Jovicic, Nemanja, Ilija Jeftic, Marina Miletic Kovacevic, Irena Tanaskovic, Nebojsa Arsenijevic, Miodrag L. Lukic, and Nada Pejnovic. "ST2 Deficiency Ameliorates High Fat Diet-Induced Liver Steatosis In BALB/c Mice." Serbian Journal of Experimental and Clinical Research 16, no. 1 (March 1, 2015): 9–20. http://dx.doi.org/10.1515/sjecr-2015-0002.
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ABSTRACTNon-alcoholic fatty liver disease (NAFLD) is strongly associated with obesity, but the molecular mechanisms of liver steatosis and its progression to non-alcoholic steatohepatitis and fibrosis are incompletely understood. Immune reactivity plays an important role in the pathogenesis of NAFLD. The IL-33/ST2 axis has a protective role in adiposity and atherosclerosis, but its role in obesity-associated metabolic disorders requires further clarification. To investigate the unresolved role of IL-33/ST2 signalling in NAFLD, we used ST2-deficient (ST2-/-) and wild type (WT) BALB/c mice maintained on a high-fat diet (HFD) for 24 weeks. HFD-fed ST2-/- mice exhibited increased weight gain, visceral adipose tissue weight and triglyceridaemia and decreased liver weight compared with diet-matched WT mice. Compared with WT mice on an HFD, ST2 deletion significantly reduced hepatic steatosis, liver inflammation and fibrosis and downregulated the expression of genes related to lipid metabolism in the liver. The frequency of innate immune cells in the liver, including CD68+ macrophages and CD11c+ dendritic cells, was lower in HFD-fed ST2-/- mice, accompanied by lower TNFα serum levels compared with diet-matched WT mice. Less collagen deposition in the livers of ST2-/- mice on an HFD was associated with lower numbers of profibrotic CD11b+Ly6clow monocytes and CD4+IL-17+ T cells in the liver, lower hepatic gene expression of procollagen, IL-33 and IL-13, and lower serum levels of IL-33 and IL-13 compared with diet-matched WT mice.Our findings suggest that the IL-33/ST2 axis may have a complex role in obesity-associated metabolic disorders. Although it is protective in HFD-induced adiposity, the IL-33/ST2 pathway promotes hepatic steatosis, inflammation and fibrosis.
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Liu, Shenbin, Wen-Li Mi, Qian Li, Meng-Ting Zhang, Ping Han, Shan Hu, Qi-Liang Mao-Ying, and Yan-Qing Wang. "Spinal IL-33/ST2 Signaling Contributes to Neuropathic Pain via Neuronal CaMKII–CREB and Astroglial JAK2–STAT3 Cascades in Mice." Anesthesiology 123, no. 5 (November 1, 2015): 1154–69. http://dx.doi.org/10.1097/aln.0000000000000850.
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Abstract Background Emerging evidence indicates that nerve damage–initiated neuroinflammation and immune responses, which are evidenced by the up-regulation of proinflammatory cytokines, contribute to the development of neuropathic pain. This study investigated the role of spinal interleukin (IL)-33 and its receptor ST2 in spared nerve injury (SNI)-induced neuropathic pain. Methods The von Frey test and acetone test were performed to evaluate neuropathic pain behaviors (n = 8 to 12), and Western blot (n = 4 to 6), immunohistochemistry, real-time polymerase chain reaction (n = 5), and Bio-Plex (n = 5) assays were performed to understand the molecular mechanisms. Results Intrathecal administration of ST2-neutralizing antibody or ST2 gene knockout (ST2−/−) significantly attenuated the SNI-induced mechanical and cold allodynia. On the 7th day after SNI, the expression of spinal IL-33 and ST2 was increased by 255.8 ± 27.3% and 266.4 ± 83.5% (mean ± SD), respectively. Mechanistic studies showed that the increased expression of the spinal N-methyl-d-aspartate (NMDA) receptor subunit 1 after SNI was reduced by ST2 antibody administration or ST2−/−. The induction of nociceptive behaviors in naive mice due to recombinant IL-33 was reversed by the noncompetitive NMDA antagonist MK-801. ST2 antibody administration or ST2−/− markedly inhibited the increased activation of the astroglial janus kinase 2 (JAK2)–signal transducer and activator of transcription 3 (STAT3) cascade and the neuronal calcium–calmodulin-dependent kinase II (CaMKII)–cyclic adenosine monophosphate response element–binding protein (CREB) cascade after SNI. Moreover, intrathecal pretreatment with the CaMKII inhibitor KN-93 or the JAK2–STAT3 cascade inhibitor AG490 attenuated recombinant IL-33-induced nociceptive behaviors and NMDA subunit 1 up-regulation in naive mice. Conclusion Spinal IL-33/ST2 signaling contributes to neuropathic pain by activating the astroglial JAK2–STAT3 cascade and the neuronal CaMKII–CREB cascade.
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Wang, Xuan, Xiaoqing Shao, Xinhao Liu, Qiu Qin, Jian Xu, and Jin A. Zhang. "Dysregulated Interleukin -33/ST2 Pathway Perpetuates Chronic Inflammation in Hashimoto’s Thyroiditis." Endocrine, Metabolic & Immune Disorders - Drug Targets 19, no. 7 (October 11, 2019): 1012–21. http://dx.doi.org/10.2174/1871530319666190226164309.
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Objective: Hashimoto’s Thyroiditis (HT) is an autoimmune disease, characterized by chronic inflammation of the thyroid gland with unknown etiologies. Recently, interleukin-33/ST2 (IL- 33/ST2) pathway reveals its participation in the process of several autoimmune diseases. In this study, the role of IL-33/ST2 pathway in the development of HT is investigated. Methods: The levels of plasma IL-33, sST2 and the frequency of circulating CD4+ST2L+T cells in 30 HT patients and 20 healthy controls were determined by enzyme-linked immunosorbent assay (ELISA) and flow cytometry respectively. The mRNA expressions of related molecules in IL-33/ST2 pathway in thyroid tissues (12 HT patients and 10 controls) were detected by real-time quantitative PCR (RTqPCR). The protein expressions of IL-33 and ST2 were determined by Western blot and immunohistochemistry staining. Results: The mRNA expressions of plasma IL-33 and sST2 were elevated in HT patients, with an increased ratio of IL-33/sST2. The number of CD4+ST2L+ T cells in PBMCs of HT group was significantly increased when compared to the control group (CON) by Flow cytometry assay. MRNA Expression of IL-33 and ST2 in thyroid tissue and the level of IL-1β and IL-18 were significantly upregulated in HT patients, while IL-5 was down-regulated in HT patients, compared to CON. The expression of IL-1β and IL-18 were positively correlated with the expression of IL-33. Results of western blot and immunohistochemical staining were consistent with qPCR. Conclusion: IL-33/ST2 pathway participates in HT via affecting the production of inflammatory cytokines.
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Obata-Ninomiya, Kazushige, Kenji Ishiwata, Yusuke Endo, Tomomi Ichikawa, Atsushi Onodera, Kiyoshi Hirahara, Yoshitaka Okamoto, Hirotaka Kanuka, Steven F. Ziegler, and Toshinori Nakayama. "CXCR5+ST2+memory Th2 cell reduced maturation and fecundity of Nippostrongylus brasiliensis through increase of expression of Major Basic Protein in eosinophils." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 229.6. http://dx.doi.org/10.4049/jimmunol.202.supp.229.6.
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Abstract Once mice experience the infection of helminth, the mice acquired resistance to the helminth. We have studied about memory responses against Nippostrongylus brasiliensis (Nb) in mice. Nb penetrates into skin, passes through the lungs and finally reaches to the gut. It has been reported that IL-33 contributes to the immune responses against re-infection of helminth. However, the IL-33-dependent immunity to Nb has not been fully defined. In this study, we identified subsets of memory Th2 (mTh2) cells; CXCR5+ST2+CD44hiTh2 cells and ST2−CD44hiTh2 cells producing IL-4 and IL-13, and increasing accumulation of eosinophils in the lungs in helminth infection. CXCR5+ST2+mTh2 cells rather than ST2− mTh2 cells strongly expressed IL-5 and increased the expression of Major Basic Protein (MBP) in eosinophils in the lungs, which is important for reduction of maturation and fecundity of Nb in the intestine. Notably, we also found ST2+Treg cells but not ST2− Treg cells can suppress the ST2+mTh2 cell-mediated reduction of fecundity of Nb. Taken together, these findings indicate that we identified a mechanism against helminth elicited by a subpopulation of IL-5-producing Th2 cells through the accumulation of eosinophils strongly expressing MBP in the lungs. This would be helpful to establish the drugs and/or vaccination against helminth,
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Ali, M., G. Zhang, W. R. Thomas, C. J. McLean, J. A. Bizzintino, I. A. Laing, A. C. Martin, J. Goldblatt, P. N. Le Souëf, and C. M. Hayden. "Investigations into the role of ST2 in acute asthma in children." Tissue Antigens 73, no. 3 (March 2009): 206–12. http://dx.doi.org/10.1111/j.1399-0039.2008.01185.x.
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St. Rose, Marie-Clare, Naomi Tsurutani, Adam Adler, and Anthony Vella. "Defining the role of the alarmin IL-33 during the CD8 T cell effector response (VAC3P.958)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 73.20. http://dx.doi.org/10.4049/jimmunol.192.supp.73.20.
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Abstract ST2, the receptor for the alarmin IL-33, is expressed on CD8 T cells and both IL-33 and ST2 can optimize anti-viral CD8 T cell immune responses. Further, signaling through ST2 in combination with innate-derived cytokines such as IL-12 can induce TCR-independent production of IFN-gamma. We sought to understand the role of the IL-33/ST2 pathway during the effector CD8 T cell response elicited after immunization with CD134 and CD137 costimulatory agonists. ST2 is rapidly up-regulated on CD27+ effector CD8 T cells during the earliest phase of T cell re-activation, even before the up-regulation of other well-known T cell activation markers. Also, CD27+ST2+ CD8 T cells expressed increased cytokines compared to CD27-veST2+ CD8 T cells, and blockade of ST2 impeded the expression of those cytokines. Moreover, CD27+ST2+ CD8 T cells can kill EL4 tumor targets. Thus, ST2 seems to be marking effector CD8 T cells with the best capacity to exert effector functions. Upon TCR engagement, viable effector CD8 T cells rapidly up-regulate ST2, which facilitates the delivery of additional activation signals through IL-33 that further augment T cell activation. Based on these findings, we hypothesize that IL-33 may be one of the first signals that link T cell activation with the local stromal environment. Thus, direct targeting of the more highly functional ST2+ CD8 T cells may improve the outcome of T cell-based cancer immunotherapies.
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Kuo, Chih-Feng, Wei-Yu Chen, Hai-Han Yu, Yu-Hsuan Tsai, Ya-Chu Chang, Chih-Peng Chang, and Nina Tsao. "IL-33/ST2 Axis Plays a Protective Effect in Streptococcus pyogenes Infection through Strengthening of the Innate Immunity." International Journal of Molecular Sciences 22, no. 19 (September 29, 2021): 10566. http://dx.doi.org/10.3390/ijms221910566.
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Group A Streptococcus (GAS) causes invasive human diseases with the cytokine storm. Interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) axis is known to drive TH2 response, while its effect on GAS infection is unclear. We used an air pouch model to examine the effect of the IL-33/ST2 axis on GAS-induced necrotizing fasciitis. GAS infection induced IL-33 expression in wild-type (WT) C57BL/6 mice, whereas the IL-33- and ST2-knockout mice had higher mortality rates, more severe skin lesions and higher bacterial loads in the air pouches than those of WT mice after infection. Surveys of infiltrating cells in the air pouch of GAS-infected mice at the early stage found that the number and cell viability of infiltrating cells in both gene knockout mice were lower than those of WT mice. The predominant effector cells in GAS-infected air pouches were neutrophils. Absence of the IL-33/ST2 axis enhanced the expression of inflammatory cytokines, but not TH1 or TH2 cytokines, in the air pouch after infection. Using in vitro assays, we found that the IL-33/ST2 axis not only enhanced neutrophil migration but also strengthened the bactericidal activity of both sera and neutrophils. These results suggest that the IL-33/ST2 axis provided the protective effect on GAS infection through enhancing the innate immunity.
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Lukic, Miodrag, Vladimir Volarevic, Eric Mensah-Brown, and Allen Shahin. "ST2 deficiency enhances the severity of Th1/Th-17 mediated inflammation (83.27)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 83.27. http://dx.doi.org/10.4049/jimmunol.184.supp.83.27.
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Abstract ST2 selectively and stably expressed on the surface of T-helper 2 (Th2) but not Th-1 cells is a ligand for recently identified Interleukin-33 (IL-33). We have studied the susceptibility to and severity of the two T cell mediated inflammatory process: multiple low dose streptozotocin induced diabetes and Con-A induced hepatitis, in ST2 deficient (ST2-/-) and “wild-type: BALB/C mice. After diabetes induction (40mg STZ/kg b.w. for 5 days) ST2-/- mice developed glycemia and glycosuria. β cell loss and intra-islet mononuclear infiltrates while “wild type” mice did not develop any biochemical signs and histology revealed only peri-insulitis. When injected with Con-A (12 mg/kg b.w) ST2-/- mice developed significantly enhanced hepatitis as evaluated by liver function test 8 and 24 hours after induction and quantitative analysis of the hepatocytes necrosis. Analysis of cellular make up of the pancreatic lymph nodes and pancreata (in diabetes) and liver infiltrating cells (in ConA induced hepatitis) and their cytokines content by FACS analysis and cytokine expression by RT-PCR revealed the enhanced infiltration of Th-1 and Th-17 cells and higher content and expression of proinflammatory cytokines: IFN-γ, IL-17 and TNF. We therefore concluded that attenuation of IL-33-ST2 axis facilitates the induction of Th-1/Th-17 mediated inflammatory autoimmunity.
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Liu, Xiaoting, Lei Wang, Jing Chen, Hongna Qi, Guoying Ma, and Weizhan Wang. "Expression of Hypersensitive Troponin I and Soluble ST2 in Acute Organophosphorus Pesticide Poisoning." Computational and Mathematical Methods in Medicine 2022 (January 27, 2022): 1–5. http://dx.doi.org/10.1155/2022/1427231.
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The role of soluble growth stimulating gene 2 protein and highly sensitive cardiac troponin in the diagnosis of early myocardial injury caused by acute organophosphorus pesticide poisoning was studied. 171 inpatients with AOPP were divided into three experimental groups according to their mild, moderate, and severe conditions. 20 healthy people were selected as the control group. The levels of cTnI, HS-CTNI, NT proBNP, and ST2 were measured at the 4th and 12th hours after the experiment. The measured data were expressed by mean standard deviation. The independent sample t -test was used for the detection between the two groups, and one-way ANOVA was used for the analysis and comparison between multiple groups. The relevant data were analyzed by Spearman correlation test ( P < 0.05 ). The levels of cTnI and HS cTnI in the experimental group increased with the extension of time and the deepening of poisoning degree; four hours after admission, ST2 and NT proBNP water in the control group and the experimental group increased significantly on average. According to the analysis of the data, there was a positive correlation between HS TnI and ST2 in patients with AOPP ( r = 0.938 , P < 0.001 , r = 0.827 , P < 0.001 ). The more serious the disease, the higher the concentrations of HS TnI and ST2, and the more serious the myocardial injury.