Citation

  • Authors: Li C. et al.
  • Year: 2022
  • Journal: Cell Death Discov 8 163
  • Applications: in vitro / siRNA / INTERFERin
  • Cell type: Adipose-derived stem cells (ADSCs)

Method

Subcutaneous ADSCs were isolated from inguinal fat of the mice at the age of 10–12 weeks as previously described [40]. Briefly, fat pads were digested with 2 mg/mL collagenase I (Worthington, Lakewood, NJ) to isolate stromal vascular fraction cells. After overnight incubation, adherent cells were cultured as ADSCs for subsequent experiments. ADSCs were treated with TNF-α (10 ng/mL) for 24 h, the cells and supernatants were collected for assay. In some experiments, ADSCs were transfected with IL-1R8 siRNA (siIL-1R8; GenePharma, Shanghai, China) using INTERFERin (Polyplus, Illkirch, France) before TNF-α stimulation.

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.

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