Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Center for Inflammation Research , Ghent, Belgium.
Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
J Exp Med. 2023 Sep 4;220(9). doi: 10.1084/jem.20210788. Epub 2023 Jun 22.
Healthy adipose tissue (AT) contains ST2+ Tregs, ILC2s, and alternatively activated macrophages that are lost in mice or humans on high caloric diet. Understanding how this form of type 2 immunity is regulated could improve treatment of obesity. The STE20 kinase Thousand And One amino acid Kinase-3 (TAOK3) has been linked to obesity in mice and humans, but its precise function is unknown. We found that ST2+ Tregs are upregulated in visceral epididymal white AT (eWAT) of Taok3-/- mice, dependent on IL-33 and the kinase activity of TAOK3. Upon high fat diet feeding, metabolic dysfunction was attenuated in Taok3-/- mice. ST2+ Tregs disappeared from eWAT in obese wild-type mice, but this was not the case in Taok3-/- mice. Mechanistically, AT Taok3-/- Tregs were intrinsically more responsive to IL-33, through higher expression of ST2, and expressed more PPARγ and type 2 cytokines. Thus, TAOK3 inhibits adipose tissue Tregs and regulates immunometabolism under excessive caloric intake.
健康的脂肪组织（AT）中含有 ST2+Tregs、ILC2 和被高卡路里饮食的小鼠或人类丢失的选择性激活的巨噬细胞。了解这种 2 型免疫的调节方式可能有助于改善肥胖症的治疗。STE20 激酶 Thousand And One amino acid Kinase-3（TAOK3）已被证明与肥胖有关，但它的确切功能尚不清楚。我们发现，Taok3-/- 小鼠的内脏附睾白色脂肪组织（eWAT）中 ST2+Tregs 上调，这依赖于 IL-33 和 TAOK3 的激酶活性。在高脂肪饮食喂养下，Taok3-/- 小鼠的代谢功能障碍得到了缓解。肥胖野生型小鼠的 eWAT 中 ST2+Tregs 消失，但 Taok3-/- 小鼠并非如此。从机制上讲，AT Taok3-/-Tregs 通过更高水平的 ST2 表达，对 IL-33 的反应更为敏感，并且表达更多的 PPARγ 和 2 型细胞因子。因此，TAOK3 抑制脂肪组织 Tregs，并在过度热量摄入下调节免疫代谢。
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