Interferon regulatory factor 4 regulates obesity-induced inflammation through regulation of adipose tissue macrophage polarization.
Interferon regulatory factor 4 regulates obesity-induced inflammation through regulation of adipose tissue macrophage polarization.
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作者：
Eguchi J;Kong X;Tenta M;Wang X;Kang S;Rosen ED
干扰素调节因子（IRFs）在免疫系统的转录调节中发挥着多种功能。我们之前已经表明，几种irf是脂肪形成的调节剂，IRF4是脂肪细胞脂质处理的关键转录调节剂。然而，IRF4在脂肪组织巨噬细胞（ATMs）中的功能作用尚不清楚，尽管在脂肪组织巨噬细胞中有高表达。本研究表明，IRF4的表达在原代巨噬细胞和高脂肪饮食诱导的肥胖小鼠的atm中受到调节。Irf4−/−巨噬细胞产生更高水平的促炎细胞因子，包括白细胞介素-1β和肿瘤坏死因子-α，以响应脂肪酸。在共培养实验中，巨噬细胞中IRF4的缺失导致3T3-L1脂肪细胞胰岛素信号传导和葡萄糖摄取减少。为了确定IRF4在肥胖背景下的巨噬细胞特异性功能，我们产生了骨髓细胞特异性IRF4敲除小鼠，尽管肥胖没有差异，但它们在高脂肪饮食中表现出显著的胰岛素抵抗。这种表型与脂肪组织、骨骼肌和肝脏中炎症基因表达增加和胰岛素信号传导减少有关。此外，Irf4−/−atm表达M1极化增强的标记物。这些发现表明，IRF4在饮食诱导的肥胖中是炎症的负调节因子，部分通过调节巨噬细胞极化。
Interferon regulatory factors (IRFs) play functionally diverse roles in the transcriptional regulation of the immune system. We have previously shown that several IRFs are regulators of adipogenesis and that IRF4 is a critical transcriptional regulator of adipocyte lipid handling. However, the functional role of IRF4 in adipose tissue macrophages (ATMs) remains unclear, despite high expression there. Here we show that IRF4 expression is regulated in primary macrophages and in ATMs of high-fat diet–induced obese mice. Irf4−/− macrophages produce higher levels of proinflammatory cytokines, including interleukin-1β and tumor necrosis factor-α, in response to fatty acids. In coculture experiments, IRF4 deletion in macrophages leads to reduced insulin signaling and glucose uptake in 3T3-L1 adipocytes. To determine the macrophage-specific function of IRF4 in the context of obesity, we generated myeloid cell–specific IRF4 knockout mice, which develop significant insulin resistance on a high-fat diet, despite no difference in adiposity. This phenotype is associated with increased expression of inflammatory genes and decreased insulin signaling in adipose tissue, skeletal muscle, and liver. Furthermore, Irf4−/− ATMs express markers suggestive of enhanced M1 polarization. These findings indicate that IRF4 is a negative regulator of inflammation in diet-induced obesity, in part through regulation of macrophage polarization.
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