IRF5 governs liver macrophage activation that promotes hepatic fibrosis in mice and humans
IRF5 governs liver macrophage activation that promotes hepatic fibrosis in mice and humans
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DOI：
10.1172/jci.insight.88689
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发表时间：
2016-12-08
期刊：
影响因子：
8
通讯作者：
Venteclef, Nicolas
中科院分区：
文献类型：
--
作者：
Alzaid, Fawaz;Lagadec, Floriane;Venteclef, Nicolas
肝纤维化是由肝脏中的炎症引起的，所述炎症由驻留的巨噬细胞活化和大量白细胞积聚引发。肝巨噬细胞在维持肝脏内稳态以及与纤维化相关的急性和慢性肝损伤的发病机制中占据中心地位。干扰素调节因子5（Interferon Regulatory Factor 5，IRF5）是近年来发现的一种重要的促炎转录因子，参与了急、慢性炎症条件下巨噬细胞的活化。在这里，我们揭示了IRF5在人类受试者的肝巨噬细胞中被显著诱导，这些受试者因非酒精性脂肪肝疾病或丙型肝炎病毒感染而发生肝纤维化。此外，IRF5表达与肝损伤的临床标志物如血浆转氨酶和胆红素水平呈正相关。有趣的是，骨髓细胞中缺乏IRF5的小鼠（MKO）受到保护，免受代谢或毒性应激诱导的肝纤维化。缺乏IRF5的巨噬细胞的转录重编程的特征在于免疫抑制和抗凋亡特性。因此，IRF5 MKO小鼠通过促进肝细胞存活来响应肝细胞应激，从而完全保护免于肝纤维化。我们的研究结果揭示了一个由IRF5控制的调控网络，它介导了小鼠和人类的肝细胞死亡和肝纤维化。因此，调节IRF5功能可能是纤维炎性肝病实验治疗的一种有吸引力的方法。
Hepatic fibrosis arises from inflammation in the liver initiated by resident macrophage activation and massive leukocyte accumulation. Hepatic macrophages hold a central position in maintaining homeostasis in the liver and in the pathogenesis of acute and chronic liver injury linked to fibrogenesis. Interferon regulatory factor 5 (IRF5) has recently emerged as an important proinflammatory transcription factor involved in macrophage activation under acute and chronic inflammation. Here, we revealed that IRF5 is significantly induced in liver macrophages from human subjects developing liver fibrosis from nonalcoholic fatty liver disease or hepatitis C virus infection. Furthermore, IRF5 expression positively correlated with clinical markers of liver damage, such as plasma transaminase and bilirubin levels. Interestingly, mice lacking IRF5 in myeloid cells (MKO) were protected from hepatic fibrosis induced by metabolic or toxic stresses. Transcriptional reprogramming of macrophages lacking IRF5 was characterized by immunosuppressive and antiapoptotic properties. Consequently, IRF5 MKO mice respond to hepatocellular stress by promoting hepatocyte survival, leading to complete protection from hepatic fibrogenesis. Our findings reveal a regulatory network, governed by IRF5, that mediates hepatocyte death and liver fibrosis in mice and humans. Therefore, modulating IRF5 function may be an attractive approach to experimental therapeutics in fibroinflammatory liver disease.