The David Rosensweig Genomics Center, Hospital for Special Surgery, 535 East 70th Street, New York, New York 10021, USA.
Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, 1300 York Avenue, New York, New York 10021, USA.
Nat Commun. 2016 Jul 28;7:12254. doi: 10.1038/ncomms12254.
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.
饮食诱导的肥胖会导致白色脂肪组织（WAT）中慢性巨噬细胞驱动的炎症，从而导致胰岛素抵抗。然而，WAT 中的巨噬细胞在起源、基因表达和活性上存在差异：与浸润的单核细胞衍生的炎性巨噬细胞不同，WAT 驻留巨噬细胞能抵抗炎症和胰岛素抵抗，但它们的转录编程机制仍知之甚少。我们最近报道称，核受体辅因子-糖皮质激素受体（GR）相互作用蛋白（GRIP）1 与 GR 合作，通过作为组织驻留巨噬细胞分化的驱动因子-Krüppel 样因子（KLF）4 的共激活剂来抑制炎症基因。在这里，我们表明 GRIP1 通过作为组织驻留巨噬细胞分化的驱动因子-Krüppel 样因子（KLF）4 的共激活剂，在 GR 独立途径中，促进 IL4 诱导的巨噬细胞编程。此外，条件性缺乏巨噬细胞中 GRIP1 的肥胖小鼠在代谢组织、脂肪肝、高血糖和胰岛素抵抗中会发生大量巨噬细胞浸润和炎症，从而再现代谢疾病。因此，GRIP1 是免疫代谢的关键调节剂，它采用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。
