IL-37 isoform D acts as an inhibitor of soluble ST2 to boost type 2 immune homeostasis in white adipose tissue

• Published in: Cell death discovery Vol. 8; no. 1; p. 163
• Main Authors: Li, Chaoze, Zhao, Mingsheng, Zhao, Ming, Chen, Nuo, Guo, Yaxin, Du, Yingxin, Zhang, Yi, Cao, Baihui, Zhan, Bing, Guo, Chun, Li, Yuan, Li, Yan, Shi, Yongyu, Zhu, Faliang, Zhang, Lining, Wang, Qun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05-04-2022; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/250/127; 631/250/256; 692/699/2743/393; Adipose tissue; Apoptosis; Biochemistry; Biomedical and Life Sciences; Body fat; Body weight loss; Cell Biology; Cell Cycle Analysis; Cytokines; Energy expenditure; High fat diet; Homeostasis; Insulin; Insulin resistance; Interleukin 1; Interleukin 1 receptors; Life Sciences; Macrophages; Metabolic disorders; NF-κB protein; Obesity; Stem cell transplantation; Stem Cells; Tumor necrosis factor-α; Tumorigenicity; Weight control
• ISSN: 2058-7716; 2058-7716
• DOI: 10.1038/s41420-022-00960-3

White adipose tissue (WAT) homeostasis substantiated by type 2 immunity is indispensable to counteract obesity and metabolic disorders. IL-33/suppression of tumorigenicity (ST) 2 signaling promotes type 2 response in WAT, while potential regulators remain to be discovered. We identified human IL-37 isoform D (IL-37D) as an effective trigger for ST2-mediated type 2 immune homeostasis in WAT. IL-37D transgene amplified ST2
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immune cells, promoted M2 macrophage polarization and type 2 cytokine secretion in WAT that mediate beiging and inflammation resolution, thereby increasing energy expenditure, reducing obesity and insulin resistance in high-fat diet (HFD)-fed mice. Mechanistically, either endogenous or exogenous IL-37D inhibited soluble ST2 (sST2) production from WAT challenged with HFD or TNF-α. Recombinant sST2 impaired the beneficial effects of IL-37D transgene in HFD-fed mice, characterized by damaged weight loss, insulin action, and type 2 cytokine secretion from WAT. In adipose-derived stem cells, IL-37D inhibited TNF-α-stimulated sST2 expression through IL-1 receptor 8 (IL-1R8)-dependent NF-κB inactivation. Collectively, human IL-37D suppresses sST2 to boost type 2 immune homeostasis in WAT, which may be a promising therapy target for obesity and metabolic disorders.