Han Yong-Hyun, Kim Hyeon-Ji, Na Hyelin, Nam Min-Woo, Kim Ju-Yeon, Kim Jun-Seok, Koo Seung-Hoi, Lee Mi-Ock
College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Department of Life Sciences, Korea University, Seoul 02841, Republic of Korea.
Cell Rep. 2017 Jul 5;20(1):124-135. doi: 10.1016/j.celrep.2017.06.017.
The regulation of M1/M2 polarization in liver macrophages is closely associated with the progression of nonalcoholic steatohepatitis (NASH); however, the mechanism involved in this process remains unclear. Here, we describe the orphan nuclear receptor retinoic-acid-related orphan receptor α (RORα) as a key regulator of M1/M2 polarization in hepatic residential Kupffer cells (KCs) and infiltrated monocyte-derived macrophages. RORα enhanced M2 polarization in KCs by inducing the kruppel-like factor 4. M2 polarization was defective in KCs and bone-marrow-derived macrophages of the myeloid-specific RORα null mice, and these mice were susceptible to HFD-induced NASH. We found that IL-10 played an important role in connecting the function of M2 KCs to lipid accumulation and apoptosis in hepatocytes. Importantly, M2 polarization was controlled by a RORα activator, JC1-40, which improved symptoms of NASH. Our results suggest that the M2-promoting effects of RORα in liver macrophages may provide better therapeutic strategies against NASH.
肝脏巨噬细胞中M1/M2极化的调节与非酒精性脂肪性肝炎（NASH）的进展密切相关；然而，这一过程涉及的机制仍不清楚。在此，我们描述了孤儿核受体视黄酸相关孤儿受体α（RORα）是肝脏驻留库普弗细胞（KCs）和浸润的单核细胞衍生巨噬细胞中M1/M2极化的关键调节因子。RORα通过诱导 kruppel样因子4增强KCs中的M2极化。在髓系特异性RORα基因敲除小鼠的KCs和骨髓来源的巨噬细胞中，M2极化存在缺陷，并且这些小鼠易患高脂饮食诱导的NASH。我们发现IL-10在将M2 KCs的功能与肝细胞中的脂质积累和凋亡联系起来方面发挥着重要作用。重要的是，M2极化受RORα激活剂JC1-40的控制，JC1-40改善了NASH的症状。我们的结果表明，RORα在肝脏巨噬细胞中促进M2的作用可能为对抗NASH提供更好的治疗策略。
