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

Abstract

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+ 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.

The multifaceted life of macrophages in white adipose tissue: Immune shift couples with metabolic switch

“…[87][88][89] In addition, Stat1 signaling, which drives M1 phenotypes, and inflammatory pathways such as nuclear factor κB signaling could be other potential targets for treating WAT inflammation and obesity-induced metabolic dysfunctions. [11][12][13]78 Indeed, baricitinib, a Jak1/Jak2 inhibitor that suppresses Stat activation, reduces WAT inflammation and improves insulin resistance in mice with HFD-induced obesity. 62,90 Aside from inflammation resolution, the inhibition of M1-like ATMs may help to restore M2-like phenotypes in ATMs, which contribute to obesity resistance and metabolic improvement.…”

A Deep View of the Biological Property of Interleukin-33 and Its Dysfunction in the Gut

“…Certain small molecules such as miR-487b [138] and SPRR3 [139] can suppress the IL-33/ST2 signaling pathway, relieving chronic heart failure and allergic asthma, respectively (Table 1). IL-37D, on the other hand, can upregulate the IL-33/ST2 signaling pathway (Table 1), participating in the regulation of obesity and metabolic disorders [140]. The p38α/β MAPK signaling pathway [141] and the Notch1 signaling pathway [142] are also associated with the response and expression of IL-33 in ILC2 and B cells (Table 1).…”

High‐fat‐diet induced obesity and diabetes mellitus in Th1 and Th2 biased mice strains: A brief overview and hypothesis

“…23,24 Several lines of evidence indicate that a Th1-type immune response promotes the development of diabetes whereas a Th2type immune response is protective for a diabetic phenotype. [25][26][27][28][29] The effect of these responses in adipose tissue and other metabolically relevant tissues may inform about the pathogenesis of obesity in mice. 26,27…”

“…[25][26][27][28][29] The effect of these responses in adipose tissue and other metabolically relevant tissues may inform about the pathogenesis of obesity in mice. 26,27…”