Flagellin-mediated activation of IL-33-ST2 signaling by a pathobiont promotes intestinal fibrosis.
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ABSTRACT:
SUBMITTER: Imai J
PROVIDER: S-EPMC6462251 | biostudies-literature | 2019 May
REPOSITORIES: biostudies-literature
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Project description:Microvascular dysfunction in the heart and its association with periarteriolar fibrosis may contribute to the diastolic dysfunction seen in heart failure with preserved ejection fraction. Interleukin-33 (IL-33) prevents global myocardial fibrosis in a pressure overloaded left ventricle by acting via its receptor, ST2 (encoded by the gene, Il1rl1); however, whether this cytokine can also modulate periarteriolar fibrosis remains unclear. We utilized two approaches to explore the role of IL-33/ST2 in periarteriolar fibrosis. First, we studied young and old wild type mice to test the hypothesis that IL-33 and ST2 expression change with age. Second, we produced pressure overload in mice deficient in IL-33 or ST2 by transverse aortic constriction (TAC). With age, IL-33 expression increased and ST2 expression decreased. These alterations accompanied increased periarteriolar fibrosis in aged mice. Mice deficient in ST2 but not IL-33 had a significant increase in periarteriolar fibrosis following TAC compared to wild type mice. Thus, loss of ST2 signaling rather than changes in IL-33 expression may contribute to periarteriolar fibrosis during aging or pressure overload, but manipulating this pathway alone may not prevent or reverse fibrosis.
| S-EPMC6402609 | biostudies-literature
Project description:Interleukin 33 (IL-33) is highly expressed in barrier sites, acting via the suppression of tumorigenicity 2 receptor (ST2). IL-33/ST2 axis has long been known to play a pivotal role in immunity and cell homeostasis by promoting wound healing and tissue repair. However, it is also involved in the loss of balance between extensive inflammation and tissue regeneration lead to remodeling, the hallmark of fibrosis. The aim of the current review is to critically evaluate the available evidence regarding the role of the IL-33/ST2 axis in organ fibrosis. The role of the axis in tissue remodeling is better understood considering its crucial role reported in organ development and regeneration. Generally, the IL-33/ST2 signaling pathway has mainly anti-inflammatory/anti-proliferative effects; however, chronic tissue injury is responsible for pro-fibrogenetic responses. Regarding pulmonary fibrosis mature IL-33 enhances pro-fibrogenic type 2 cytokine production in an ST2- and macrophage-dependent manner, while full-length IL-33 is also implicated in the pulmonary fibrotic process in an ST2-independent, Th2-independent fashion. In liver fibrosis, evidence indicate that when acute and massive liver damage occurs, the release of IL-33 might act as an activator of tissue-protective mechanisms, while in cases of chronic injury IL-33 plays the role of a hepatic fibrotic factor. IL-33 signaling has also been involved in the pathogenesis of acute and chronic pancreatitis. Moreover, IL-33 could be used as an early marker for ulcer-associated activated fibroblasts and myofibroblast trans-differentiation; thus one cannot rule out its potential role in inflammatory bowel disease-associated fibrosis. Similarly, the upregulation of the IL-33/ST2 axismay contribute to tubular cell injury and fibrosis via epithelial to mesenchymal transition (EMT) of various cell types in the kidneys. Of note, IL-33 exerts a cardioprotective role via ST2 signaling, while soluble ST2 has been demonstrated as a marker of myocardial fibrosis. Finally, IL-33 is a crucial cytokine in skin pathology responsible for abnormal fibroblast proliferation, leukocyte infiltration and morphologic differentiation of human endothelial cells. Overall, emerging data support a novel contribution of the IL-33/ST2 pathway in tissue fibrosis and highlight the significant role of the Th2 pattern of immune response in the pathophysiology of organ fibrosis.
| S-EPMC6207585 | biostudies-other
Project description:Mast cells (MC) are potent innate immune cells that accumulate in chronically inflamed tissues. MC express the IL-33 receptor IL-1 receptor-related protein ST2 at high level, and this IL-1 family cytokine both activates MC directly and primes them to respond to other proinflammatory signals. Whether IL-33 and ST2 play a role in MC survival remains to be defined. In skin-derived human MC, we found that IL-33 attenuated MC apoptosis without altering proliferation, an effect mediated principally through the antiapoptotic molecule B-cell lymphoma-X large (BCLXL). Murine MC demonstrated a similar mechanism, dependent entirely on ST2. In line with these observations, St2(-/-) mice exhibited reduced numbers of tissue MC in inflamed arthritic joints, in helminth-infected intestine, and in normal peritoneum. To confirm an MC-intrinsic role for ST2 in vivo, we performed peritoneal transfer of WT and St2(-/-) MC. In St2(-/-) hosts treated with IL-33 and in WT hosts subjected to thioglycollate peritonitis, WT MC displayed a clear survival advantage over coengrafted St2(-/-) MC. IL-33 blockade specifically attenuated this survival advantage, confirming IL-33 as the relevant ST2 ligand mediating MC survival in vivo. Together, these data reveal a cell-intrinsic role for the IL-33/ST2 axis in the regulation of apoptosis in MC, identifying thereby a previously unappreciated pathway supporting expansion of the MC population with inflammation.
| S-EPMC4104908 | biostudies-other
Project description:Idiopathic pulmonary fibrosis is a progressive, devastating, and yet untreatable fibrotic disease of unknown origin. Interleukin-33 (IL-33), an IL-1 family member acts as an alarmin with pro-inflammatory properties when released after stress or cell death. Here, we investigated the role of IL-33 in the bleomycin (BLM)-induced inflammation and fibrosis model using mice IL-33 receptor [chain suppression of tumorigenicity 2 (ST2)] mice compared with C57BL/6 wild-type mice. Unexpectedly, 24 h post-BLM treatment ST2-deficient mice displayed augmented inflammatory cell recruitment, in particular by neutrophils, together with enhanced levels of chemokines and remodeling factors in the bronchoalveolar space and/or the lungs. At 11 days, lung remodeling and fibrosis were decreased with reduced M2 macrophages in the lung associated with M2-like cytokine profile in ST2-deficient mice, while lung cellular inflammation was decreased but with fluid retention (edema) increased. In vivo magnetic resonance imaging (MRI) analysis demonstrates a rapid development of edema detectable at day 7, which was increased in the absence of ST2. Our results demonstrate that acute neutrophilic pulmonary inflammation leads to the development of an IL-33/ST2-dependent lung fibrosis associated with the production of M2-like polarization. In addition, non-invasive MRI revealed enhanced inflammation with lung edema during the development of pulmonary inflammation and fibrosis in absence of ST2.
| S-EPMC6026799 | biostudies-literature
Project description:Tenascin-C (TNC), a very large multimeric glycoprotein, is overexpressed in human glioblastomas, leading to a highly motile and invasive phenotype of glioma cells. However, the regulation of TNC expression in glioma has remained unclear until now. Our data suggest that interleukin-33 (IL-33) may promote the accumulation of TNC protein by autocrine or paracrine modes of action in glioma. In the present study, the expression levels of TNC, IL-33, and ST2 were measured in glioma tissue specimens, and the impact of altered IL-33 expression on TNC was investigated in vitro and in vivo. In contrast with control treatment, IL-33 treatment increased TNC expression, and knockdown of IL-33 attenuated TNC expression in glioma cells. Furthermore, IL-33 induced the activation of nuclear factor κB (NF-κB) and increased the expression of TNC in U251 cells. In addition, blockage of the IL-33-ST2-NFκB pathway resulted in downregulation of TNC production. IL-33 promoted glioma cell invasion by stimulating the secretion of TNC. Similarly, knockdown of TNC inhibited the invasiveness of glioma cells. These findings provide a novel perspective on the role of the IL-33/NF-κB/TNC signalling pathway in supporting cancer progression. Thus, targeting the IL-33/NF-κB/TNC signalling pathway may be a useful therapeutic approach in glioma.
| S-EPMC6937274 | biostudies-literature
Project description:Colorectal cancer (CRC) develops through a multistep process and is modulated by inflammation. However, the inflammatory pathways that support intestinal tumors at different stages remain incompletely understood. Interleukin (IL)-33 signaling plays a role in intestinal inflammation, yet its contribution to the pathogenesis of CRC is unknown. Using immunohistochemistry on 713 resected human CRC specimens, we show here that IL-33 and its receptor ST2 are expressed in low-grade and early-stage human CRCs, and to a lesser extent in higher-grade and more advanced-stage tumors. In a mouse model of CRC, ST2-deficiency protects from tumor development. Moreover, bone marrow (BM) chimera studies indicate that engagement of the IL-33/ST2 pathway on both the radio-resistant and radio-sensitive compartment is essential for CRC development. Mechanistically, activation of IL-33/ST2 signaling compromises the integrity of the intestinal barrier and triggers the production of pro-tumorigenic IL-6 by immune cells. Together, this data reveals a tumor-promoting role of IL-33/ST2 signaling in CRC.
| S-EPMC4760343 | biostudies-other
Project description:The suppression of tumorigenicity 2/IL-33 (ST2/IL-33) pathway has been implicated in several immune and inflammatory diseases. ST2 is produced as 2 isoforms. The membrane-bound isoform (ST2L) induces an immune response when bound to its ligand, IL-33. The other isoform is a soluble protein (sST2) that is thought to be a decoy receptor for IL-33 signaling. Elevated sST2 levels in serum are associated with an increased risk for cardiovascular disease. We investigated the determinants of sST2 plasma concentrations in 2,991 Framingham Offspring Cohort participants. While clinical and environmental factors explained some variation in sST2 levels, much of the variation in sST2 production was driven by genetic factors. In a genome-wide association study (GWAS), multiple SNPs within IL1RL1 (the gene encoding ST2) demonstrated associations with sST2 concentrations. Five missense variants of IL1RL1 correlated with higher sST2 levels in the GWAS and mapped to the intracellular domain of ST2, which is absent in sST2. In a cell culture model, IL1RL1 missense variants increased sST2 expression by inducing IL-33 expression and enhancing IL-33 responsiveness (via ST2L). Our data suggest that genetic variation in IL1RL1 can result in increased levels of sST2 and alter immune and inflammatory signaling through the ST2/IL-33 pathway.
| S-EPMC3784527 | biostudies-literature
Project description:BackgroundLoss-of-function of PD-L1 induces therapy resistance of anti-PD-1/L1 therapy, and the complex regulatory mechanisms are not completely understood. We previously reported that stroma-derived interleukin-33 (IL-33) promoted the progression of oral squamous cell carcinoma (OSCC). We here focused on the immune-regulation role of IL-33 and its receptor ST2 signaling in PD-L1-positive OSCC patients.MethodsActivated T cells in in situ and peripheral blood were analyzed by IL-33/ST3 expression. Knockdown or overexpression of ST2 combined with IL-33/IFN-γ stimulation were performed to determine PD-L1 expression and PD-L1-dependent immune escape in OSCC/human T cells co-culture system, and OSCC orthotopic model based on humanized mouse with immune reconstitution and C57BL/6 mice models.ResultsHigh IL-33/ST2 correlated with less activated T cells infiltration in situ and peripheral blood. Knockdown of ST2 down-regulated constitutive PD-L1 expression, whereas ST2 also promoted IL-33-induced PD-L1 Mechanistically, IL-33/ST2 activated JAK2/STAT3 pathway to directly promoted PD-L1 expression, and also activated MyD88/NF-κB signaling to up-regulate IFN-γ receptor (IFN-γR), which indirectly strengthen IFN-γ-induced PD-L1. Furthermore, ST2 is required for PD-L1-mediated immune tolerance in vitro and in vivo. ST2high OSCC patients have more PD-L1 and IFN-γR level in situ.ConclusionsIL-33/ST2 signaling enhanced PD-L1-mediated immune escape, ST2high OSCC patients might benefit from anti-PD-1/L1 therapy.
| S-EPMC9977940 | biostudies-literature
Project description:ST2 is an IL-1 receptor family member with transmembrane (ST2L) and soluble (sST2) isoforms. sST2 is a mechanically induced cardiomyocyte protein, and serum sST2 levels predict outcome in patients with acute myocardial infarction or chronic heart failure. Recently, IL-33 was identified as a functional ligand of ST2L, allowing exploration of the role of ST2 in myocardium. We found that IL-33 was a biomechanically induced protein predominantly synthesized by cardiac fibroblasts. IL-33 markedly antagonized angiotensin II- and phenylephrine-induced cardiomyocyte hypertrophy. Although IL-33 activated NF-kappaB, it inhibited angiotensin II- and phenylephrine-induced phosphorylation of inhibitor of NF-kappa B alpha (I kappa B alpha) and NF-kappaB nuclear binding activity. sST2 blocked antihypertrophic effects of IL-33, indicating that sST2 functions in myocardium as a soluble decoy receptor. Following pressure overload by transverse aortic constriction (TAC), ST2(-/-) mice had more left ventricular hypertrophy, more chamber dilation, reduced fractional shortening, more fibrosis, and impaired survival compared with WT littermates. Furthermore, recombinant IL-33 treatment reduced hypertrophy and fibrosis and improved survival after TAC in WT mice, but not in ST2(-/-) littermates. Thus, IL-33/ST2 signaling is a mechanically activated, cardioprotective fibroblast-cardiomyocyte paracrine system, which we believe to be novel. IL-33 may have therapeutic potential for beneficially regulating the myocardial response to overload.
| S-EPMC1865027 | biostudies-literature
Project description:Interleukin (IL)-33 is a cytokine of the IL-1 family, which signals through the ST2 receptor. Previous work demonstrated that the systemic administration of recombinant IL-33 reduces the development of atherosclerosis in apolipoprotein E-deficient (ApoE(-/-)) mice by inducing a Th1-to-Th2 shift. The objective of our study was to examine the role of endogenous IL-33 and ST2 in atherosclerosis. ApoE(-/-), IL-33(-/-)ApoE(-/-), and ST2(-/-)ApoE(-/-) mice were fed with a cholesterol-rich diet for 10 weeks. Additionally, a group of ApoE(-/-) mice was injected with a neutralizing anti-ST2 or an isotype control antibody during the period of the cholesterol-rich diet. Atherosclerotic lesion development was measured by Oil Red O staining in the thoracic-abdominal aorta and the aortic sinus. There were no significant differences in the lipid-staining area of IL-33(-/-)ApoE(-/-), ST2(-/-)ApoE(-/-), or anti-ST2 antibody-treated ApoE(-/-) mice, compared to ApoE(-/-) controls. The absence of IL-33 signaling had no major and consistent impact on the Th1/Th2 cytokine responses in the supernatant of in vitro-stimulated lymph node cells. In summary, deficiency of the endogenously produced IL-33 and its receptor ST2 does not impact the development of atherosclerosis in ApoE-deficient mice.
| S-EPMC4578523 | biostudies-literature