Itaconate and itaconate derivatives target JAK1 to suppress alternative activation of macrophages
Itaconate and itaconate derivatives target JAK1 to suppress alternative activation of macrophages
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DOI：
10.1016/j.cmet.2022.02.002
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发表时间：
2022-03-01
期刊：
影响因子：
29
通讯作者：
O'Neill, Luke A. J.
中科院分区：
文献类型：
--
作者：
Runtsch, Marah C.;Angiari, Stefano;O'Neill, Luke A. J.
克雷布斯循环衍生代谢物衣康酸及其衍生物抑制促炎的“M1”巨噬细胞的炎症反应。然而，交替激活的“M2”巨噬细胞可以摄取衣康酸。因此，我们研究了衣康酸和4-辛基衣康酸(OI)对M2巨噬细胞活化的影响。我们证明衣康酸和OI抑制M2极化和代谢重塑。IL-4信号转导检测显示，衣康酸和OI均抑制JAK1和STAT6的磷酸化。OI还可抑制巨噬细胞和辅助性T细胞(Th2)对IL-13、干扰素-β和干扰素-γ的JAK1激活。重要的是，JAK1直接被衣康酸衍生物修饰在多个残基上，包括半胱氨酸715、816、943和1130。衣康酸和OI也能抑制JAK1的活性。最后，OI处理抑制了体内M2巨噬细胞极化和JAK1的磷酸化。因此，我们确定衣康酸和OI为JAK1抑制剂，建议了一种新的策略来抑制M2巨噬细胞驱动的疾病中的JAK1。
The Krebs cycle-derived metabolite itaconate and its derivatives suppress the inflammatory response in pro-inflammatory "M1" macrophages. However, alternatively activated "M2" macrophages can take up itaconate. We therefore examined the effect of itaconate and 4-octyl itaconate (OI) on M2 macrophage activation. We demonstrate that itaconate and OI inhibit M2 polarization and metabolic remodeling. Examination of IL-4 signaling revealed inhibition of JAK1 and STAT6 phosphorylation by both itaconate and OI. JAK1 activation was also inhibited by OI in response to IL-13, interferon-beta, and interferon-gamma in macrophages and in T helper 2 (Th2) cells. Importantly, JAK1 was directly modified by itaconate derivatives at multiple residues, including cysteines 715, 816, 943, and 1130. Itaconate and OI also inhibited JAK1 kinase activity. Finally, OI treatment suppressed M2 macrophage polarization and JAK1 phosphorylation in vivo. We therefore identify itaconate and OI as JAK1 inhibitors, suggesting a new strategy to inhibit JAK1 in M2 macrophage-driven diseases.