Critical roles of interleukin-33/suppression of tumorigenicity 2 (IL-33/ST2) in pulmonary disorders.
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ABSTRACT:
SUBMITTER: Xu J
PROVIDER: S-EPMC9481433 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
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Critical roles of interleukin-33/suppression of tumorigenicity 2 (IL-33/ST2) in pulmonary disorders.
Chinese medical journal 20220620 12
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Project description:Idiopathic inflammatory myopathies (IIM) are rare connective tissue diseases, which can lead to internal organ involvement. IL-33/ST2 pathway is involved in the pathogenesis of numerous diseases including autoimmune disorders. IL-33 fulfils cardioprotective function, while soluble ST2 (sST2) is a decoy receptor that reduces protective impact of IL-33. The aim of the study was to evaluate the concentrations of sST2 and IL-33 in sera of patients with IIM and evaluate its associations with the clinical course of the disease. Patients with IIM as well as age- and sex-matched healthy controls were recruited. Concentrations of sST2 and IL-33 were assessed with ELISA in sera of both patients and controls. Patients were asked to fill in the questionnaires concerning clinical symptoms and physical functioning. Concentrations of sST2 and IL-33 were correlated with the results of laboratory tests and clinical symptoms. Concentrations of sST2 were significantly higher in IIM group than in healthy subjects (median sST2 in IIM 26.51 vs in healthy controls 21.39; p = 0.03). In the majority of patients, IL-33 concentrations did not exceed the detection limit. Anti-SRP-positive patients presented significantly higher concentrations of sST2 as compared to anti-SRP-negative patients (p = 0.04). In patients with anti-Ro52 antibodies, sST2 concentrations were significantly lower than in anti-Ro52-negative patients (p = 0.02). Concentrations of sST2 correlated with the degree of disability evaluated with Health Assessment Questionnaire. sST2 is increased in patients with IIM and its concentration correlates with the degree of disability. In patients with anti-SRP antibodies, levels of sST2 are exceptionally high.
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Project description:Interleukin-33 (IL-33), an important member of the IL-1 family, plays a pivotal role in regulating immune responses via combining with its receptor suppression of tumorigenicity 2 (ST2). We have already known IL-33/ST2 axis participates in the pathogenesis of various diseases, including liver diseases, renal diseases, and neurological diseases. Recently, emerging studies are indicating that IL-33/ST2 is also involved in a wide range of ocular diseases, such as allergic eye disease, keratitis and corneal regeneration, dry eye disease, uveitis, vitreoretinal diseases, and neuromyelitis optica spectrum disorder. In this review, we will summarize and discuss the current understanding about the functional roles of IL-33/ST2 in eyes, with an attempt to explore the possible study perspectives and therapeutic alternatives in the future.
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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.
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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.
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Project description:Interleukin-33 (IL-33) is a member of the interleukin-1 cytokine family. Its function in regulating microglial M1/M2 polarization in neuromyelitis optica spectrum disorder (NMOSD) is still unelucidated. To evaluate the role of IL-33 in NMOSD, we constructed NMOSD mice model by injecting purified serum IgG from AQP4-IgG seropositive NMOSD patients into experimental autoimmune encephalomyelitis (EAE) mice, and IL-33 was intraperitoneally injected into NMOSD mice 3 d before the model induction. We found that pretreatment of the NMOSD mice with IL-33 relieved brain neuron loss, and demyelination and improved the structure of axons, astrocytes, and mitochondria. In the neuronal and microglial coculture system, pretreatment with IL-33 in microglia alleviated NMOSD serum-induced inflammation and damaged morphology in cultured neurons. IL-33 transformed microglia to the M2 phenotype, and NMOSD serum promoted microglia to the M1 phenotype in cultured BV2 cells. Moreover, IL-33 influenced microglial polarity via the IL-33/ST2 pathway. IL-33 may be a novel insight useful for further developing NMOSD-targeted therapy and drug development.
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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:Regulatory T (Treg) cells dampen an exaggerated immune response to viral infections in order to avoid immunopathology. Cytomegaloviruses (CMVs) are herpesviruses usually causing asymptomatic infection in immunocompetent hosts and induce strong cellular immunity which provides protection against CMV disease. It remains unclear how these persistent viruses manage to avoid induction of immunopathology not only during the acute infection but also during life-long persistence and virus reactivation. This may be due to numerous viral immunoevasion strategies used to specifically modulate immune responses but also induction of Treg cells by CMV infection. Here we demonstrate that liver Treg cells are strongly induced in mice infected with murine CMV (MCMV). The depletion of Treg cells results in severe hepatitis and liver damage without alterations in the virus load. Moreover, liver Treg cells show a high expression of ST2, a cellular receptor for tissue alarmin IL-33, which is strongly upregulated in the liver of infected mice. We demonstrated that IL-33 signaling is crucial for Treg cell accumulation after MCMV infection and ST2-deficient mice show a more pronounced liver pathology and higher mortality compared to infected control mice. These results illustrate the importance of IL-33 in the suppressive function of liver Treg cells during CMV infection.
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Project description:Pulmonary arterial hypertension (PAH) is associated with significant morbidity and mortality. PAH is characterized by pulmonary artery remodeling, elevated right ventricular pressure (RVP) and, ultimately, cardiac failure. Pulmonary endothelial cells can sense danger or damage caused by mechanical injury or pathogens through alarmin cytokines. These cytokines can signal proliferation to restore barrier integrity or aberrant hyperproliferation and remodeling. We hypothesized that IL-33 signals pulmonary artery endothelial cells to proliferate under hypertensive conditions during the remodeling response and rise in RVP. To test this hypothesis, pulmonary hypertension (PH) was induced in C57Bl/6J, IL-33 receptor gene deleted (ST2-/- ) and MYD88 gene deleted (MYD88-/- ) mice by exposure to 10% O2 and SU5416 injections (SUHX). RVP, arterial wall thickness, endothelial cell proliferation and IL-33 levels and signaling were evaluated. In response to SUHX. RVP increased in C57Bl/6J mice in response to SUHX (49% male and 70% female; p < 0.0001) and this SUHX response was attenuated in ST2-/- mice (29% male p = 0.003; 30% female p = 0.001) and absent in MYD88-/- mice. Wall thickness was increased in SUHX C57Bl/6J mice (p = 0.005), but not in ST2-/- or MYD88-/- mice. Proliferating cells were detected in C57Bl/6J mice by flow cytometry (CD31+ /BrDU+ ; p = 0.02) and immunofluorescence methods (Ki-67+). IL-33 was increased by SUHX (p = 0.03) but a genotype effect was not observed (p = 0.76). We observed that in hPAECs, IL-33 expression is regulated by both IL-33 and DLL4. These data suggest IL-33/ST2 signaling is essential for the endothelial cell proliferative response in PH.
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Project description:Mature IL-33 (MIL33) acting through its receptor, ST2, is known to regulate fibrosis. The precursor, full-length IL-33 (FLIL33), may function differently from MIL33 and independently of ST2. Here we report that genetic deletion of either IL-33 or ST2 attenuates pulmonary fibrosis in the bleomycin model, as does Cre-induced IL-33 deficiency in response to either acute or chronic bleomycin challenge. However, adenovirus-mediated gene delivery of FLIL33, but not MIL33, to the lungs of either wild-type or ST2-deficient mice potentiates the profibrotic effect of bleomycin without inducing a Th2 phenotype. In cultured mouse lung cells, FLIL33 overexpression induces moderate and distinct transcriptomic changes compared with a robust response induced by MIL33, whereas ST2 deletion abrogates the effects of both IL-33 forms. Thus, FLIL33 may contribute to fibrosis in an ST2-independent, Th2-independent, non-transcriptomic fashion, suggesting that pharmacological targeting of both FLIL33 and MIL33 may prove efficacious in patients with pulmonary fibrosis.
| S-EPMC9909894 | biostudies-literature
Project description:For placental mammals, the transition from the in utero maternal environment to postnatal life requires the activation of thermogenesis to maintain their core temperature. This is primarily accomplished by induction of uncoupling protein 1 (UCP1) in brown and beige adipocytes, the principal sites for uncoupled respiration. Despite its importance, how placental mammals license their thermogenic adipocytes to participate in postnatal uncoupled respiration is not known. Here, we provide evidence that the "alarmin" IL-33, a nuclear cytokine that activates type 2 immune responses, licenses brown and beige adipocytes for uncoupled respiration. We find that, in absence of IL-33 or ST2, beige and brown adipocytes develop normally but fail to express an appropriately spliced form of Ucp1 mRNA, resulting in absence of UCP1 protein and impairment in uncoupled respiration and thermoregulation. Together, these data suggest that IL-33 and ST2 function as a developmental switch to license thermogenesis during the perinatal period. PAPERCLIP.
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