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IL-33/Regulatory T-Cell Axis Suppresses Skin Fibrosis.

ABSTRACT: Fibrosis is a pathological hallmark of systemic sclerosis, a deadly autoimmune disease affecting the connective tissues of multiple organs. However, the immune mechanisms underlying fibrosis and systemic sclerosis remain unclear. To determine the initiating immune pathway in fibrosis, we investigated the role of type 2 alarmin cytokines in the mouse model of skin fibrosis. Wild-type mice that received subcutaneous bleomycin injections developed skin fibrosis accompanied by elevated IL-33 expression in the dermis. Likewise, we found IL-33 upregulation in human skin fibrosis. Mice with germline deletion of IL-33 receptor (ST2 knockout) showed markedly exacerbated skin fibrosis in association with significantly increased T helper 2 cell to regulatory T-cell ratio in the skin. Mice that lacked ST2 specifically on regulatory T cells (Foxp3^Cre,ST2^flox/flox) showed significantly worse skin fibrosis, increased T helper 2 to regulatory T cell ratio and IL-13 expression in the skin compared with wild-type mice. Our findings show that IL-33 cytokine signaling to regulatory T cells suppresses skin fibrosis and highlight a potential therapeutic axis to alleviate the debilitating manifestations of systemic sclerosis.

SUBMITTER: Cheon SY

PROVIDER: S-EPMC9511765 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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IL-33/Regulatory T-Cell Axis Suppresses Skin Fibrosis.

Cheon Se Yun SY Park Jong Ho JH Ameri Amir H AH Lee Richard T RT Nazarian Rosalynn M RM Demehri Shadmehr S

The Journal of investigative dermatology 20220325 10

Fibrosis is a pathological hallmark of systemic sclerosis, a deadly autoimmune disease affecting the connective tissues of multiple organs. However, the immune mechanisms underlying fibrosis and systemic sclerosis remain unclear. To determine the initiating immune pathway in fibrosis, we investigated the role of type 2 alarmin cytokines in the mouse model of skin fibrosis. Wild-type mice that received subcutaneous bleomycin injections developed skin fibrosis accompanied by elevated IL-33 express ...[more]

PMID: 35341735

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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.

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IL-33/Regulatory T-Cell Axis Suppresses Skin Fibrosis.

Publications

IL-33/Regulatory T-Cell Axis Suppresses Skin Fibrosis.

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