RORα Induces KLF4-Mediated M2 Polarization in the Liver Macrophages that Protect against Nonalcoholic Steatohepatitis
RORα Induces KLF4-Mediated M2 Polarization in the Liver Macrophages that Protect against Nonalcoholic Steatohepatitis
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DOI：
10.1016/j.celrep.2017.06.017
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发表时间：
2017-07-05
期刊：
影响因子：
8.8
通讯作者：
Lee, Mi-Ock
中科院分区：
文献类型：
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作者：
Han, Yong-Hyun;Kim, Hyeon-Ji;Lee, Mi-Ock
肝脏巨噬细胞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，参与该过程的机制仍不清楚。在这里，我们描述了孤儿核受体视黄酸相关孤儿受体α（ROR α）作为肝脏住宅枯否细胞（KCs）和浸润的单核细胞衍生的巨噬细胞中M1/M2极化的关键调节因子。ROR α通过诱导Kruppel样因子4增强KC中的M2极化。骨髓特异性ROR α缺失小鼠的KC和骨髓源性巨噬细胞中M2极化缺陷，这些小鼠对HFD诱导的NASH易感。我们发现IL-10在连接M2 KCs的功能与肝细胞中的脂质积聚和凋亡中起重要作用。重要的是，M2极化由ROR α激活剂JC 1 -40控制，其改善NASH的症状。我们的研究结果表明，ROR α在肝脏巨噬细胞中的M2促进作用可能提供更好的NASH治疗策略。
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 alpha (ROR alpha) as a key regulator of M1/M2 polarization in hepatic residential Kupffer cells (KCs) and infiltrated monocyte-derived macrophages. ROR alpha 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 ROR alpha 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 ROR alpha activator, JC1-40, which improved symptoms of NASH. Our results suggest that the M2-promoting effects of ROR alpha in liver macrophages may provide better therapeutic strategies against NASH.