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TRAF4 is crucial for ST2+ memory Th2 cell expansion in IL-33-driven airway inflammation.

ABSTRACT: Tumor necrosis factor receptor-associated factor 4 (TRAF4) is an important regulator of type 2 responses in the airway; however, the underlying cellular and molecular mechanisms remain elusive. Herein, we generated T cell-specific TRAF4-deficient (CD4-cre Traf4fl/fl) mice and investigated the role of TRAF4 in memory Th2 cells expressing IL-33 receptor (ST2, suppression of tumorigenicity 2) (ST2+ mTh2 cells) in IL-33-mediated type 2 airway inflammation. We found that in vitro-polarized TRAF4-deficient (CD4-cre Traf4fl/fl) ST2+ mTh2 cells exhibited decreased IL-33-induced proliferation as compared with TRAF4-sufficient (Traf4fl/fl) cells. Moreover, CD4-cre Traf4fl/fl mice showed less ST2+ mTh2 cell proliferation and eosinophilic infiltration in the lungs than Traf4fl/fl mice in the preclinical models of IL-33-mediated type 2 airway inflammation. Mechanistically, we discovered that TRAF4 was required for the activation of AKT/mTOR and ERK1/2 signaling pathways as well as the expression of transcription factor Myc and nutrient transporters (Slc2a1, Slc7a1, and Slc7a5), signature genes involved in T cell growth and proliferation, in ST2+ mTh2 cells stimulated by IL-33. Taken together, the current study reveals a role of TRAF4 in ST2+ mTh2 cells in IL-33-mediated type 2 pulmonary inflammation, opening up avenues for the development of new therapeutic strategies.

SUBMITTER: Xiao J

PROVIDER: S-EPMC10561728 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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TRAF4 is crucial for ST2+ memory Th2 cell expansion in IL-33-driven airway inflammation.

Xiao Jianxin J Chen Xing X Liu Weiwei W Qian Wen W Bulek Katarzyna K Hong Lingzi L Miller-Little William W Li Xiaoxia X Liu Caini C

JCI insight 20230922 18

Tumor necrosis factor receptor-associated factor 4 (TRAF4) is an important regulator of type 2 responses in the airway; however, the underlying cellular and molecular mechanisms remain elusive. Herein, we generated T cell-specific TRAF4-deficient (CD4-cre Traf4fl/fl) mice and investigated the role of TRAF4 in memory Th2 cells expressing IL-33 receptor (ST2, suppression of tumorigenicity 2) (ST2+ mTh2 cells) in IL-33-mediated type 2 airway inflammation. We found that in vitro-polarized TRAF4-defi ...[more]

PMID: 37607012

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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.

Dataset Information

TRAF4 is crucial for ST2+ memory Th2 cell expansion in IL-33-driven airway inflammation.

Publications

TRAF4 is crucial for ST2+ memory Th2 cell expansion in IL-33-driven airway inflammation.

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