IRF5 governs liver macrophage activation that promotes hepatic fibrosis in mice and humans

JCI Insight. 2016 Dec 8;1(20):e88689. doi: 10.1172/jci.insight.88689.


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.

MeSH terms

  • Animals
  • Apoptosis
  • Bilirubin / blood
  • Female
  • Hepatocytes / pathology
  • Humans
  • Inflammation / pathology*
  • Interferon Regulatory Factors / metabolism*
  • Liver Cirrhosis / pathology*
  • Macrophage Activation*
  • Macrophages / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Cells / metabolism
  • Transaminases / blood


  • IRF5 protein, human
  • Interferon Regulatory Factors
  • Irf5 protein, mouse
  • Transaminases
  • Bilirubin