The transcriptional coregulator GRIP1 controls macrophage polarization and metabolic homeostasis.
The transcriptional coregulator GRIP1 controls macrophage polarization and metabolic homeostasis.
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DOI：
10.1038/ncomms12254
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发表时间：
2016-07-28
影响因子：
16.6
通讯作者：
Rogatsky I
中科院分区：
文献类型：
--
作者：
Coppo M;Chinenov Y;Sacta MA;Rogatsky I
饮食诱导的肥胖引起白色脂肪组织（WAT）的慢性巨噬细胞驱动炎症，导致胰岛素抵抗。然而，WAT巨噬细胞在其起源、基因表达和活性方面有所不同：与浸润性单核细胞衍生的炎症性巨噬细胞不同，WAT巨噬细胞可抵抗炎症和胰岛素抵抗，然而，其转录编程的机制尚不清楚。我们最近报道了一种核受体辅助因子-糖皮质激素受体（GR）相互作用蛋白（GRIP）1与GR合作抑制炎症基因。在这里，我们发现GRIP1通过gr独立的途径促进巨噬细胞编程以响应IL4，作为kruppel样因子（KLF）4的辅助激活因子，KLF 4是组织内巨噬细胞分化的驱动因素。此外，巨噬细胞条条性缺乏GRIP1的肥胖小鼠在代谢组织、脂肪肝、高血糖和胰岛素抵抗中发生大量巨噬细胞浸润和炎症，再现代谢性疾病。因此，GRIP1是免疫代谢的关键调节因子，它参与不同的转录机制来协调巨噬细胞群体之间的平衡，最终促进代谢稳态。GRIP1与糖皮质激素受体协同抑制炎症基因。在这里，作者表明GRIP1还通过促进klf4驱动的激活来响应IL-4，从而控制巨噬细胞极化，并且巨噬细胞中缺乏GRIP1的小鼠在高脂肪饮食中会出现严重的代谢功能障碍。
Diet-induced obesity causes chronic macrophage-driven inflammation in white adipose tissue (WAT) leading to insulin resistance. WAT macrophages, however, differ in their origin, gene expression and activities: unlike infiltrating monocyte-derived inflammatory macrophages, WAT-resident macrophages counteract inflammation and insulin resistance, yet, the mechanisms underlying their transcriptional programming remain poorly understood. We recently reported that a nuclear receptor cofactor—glucocorticoid receptor (GR)-interacting protein (GRIP)1—cooperates with GR to repress inflammatory genes. Here, we show that GRIP1 facilitates macrophage programming in response to IL4 via a GR-independent pathway by serving as a coactivator for Kruppel-like factor (KLF)4—a driver of tissue-resident macrophage differentiation. Moreover, obese mice conditionally lacking GRIP1 in macrophages develop massive macrophage infiltration and inflammation in metabolic tissues, fatty livers, hyperglycaemia and insulin resistance recapitulating metabolic disease. Thus, GRIP1 is a critical regulator of immunometabolism, which engages distinct transcriptional mechanisms to coordinate the balance between macrophage populations and ultimately promote metabolic homeostasis. GRIP1 cooperates with the glucocorticoid receptor to repress inflammatory genes. Here the authors show that GRIP1 also controls macrophage polarization, by promoting KLF4-driven activation in response to IL-4, and that mice lacking GRIP1 in macrophages develop severe metabolic dysfunction on a high-fat diet.