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IRF5 governs liver macrophage activation that promotes hepatic fibrosis in mice and humans
Fawaz Alzaid, … , Fabienne Foufelle, Nicolas Venteclef
Fawaz Alzaid, … , Fabienne Foufelle, Nicolas Venteclef
Published December 8, 2016
Citation Information: JCI Insight. 2016;1(20):e88689. https://doi.org/10.1172/jci.insight.88689.
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Research Article Hepatology Inflammation

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

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Abstract

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.

Authors

Fawaz Alzaid, Floriane Lagadec, Miguel Albuquerque, Raphaëlle Ballaire, Lucie Orliaguet, Isabelle Hainault, Corinne Blugeon, Sophie Lemoine, Agnès Lehuen, David G. Saliba, Irina A. Udalova, Valérie Paradis, Fabienne Foufelle, Nicolas Venteclef

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Figure 1

IRF5 is expressed in human hepatic macrophages and is induced in human NASH and hepatic fibrosis.

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IRF5 is expressed in human hepatic macrophages and is induced in human N...
(A) Interferon regulatory factor 5 (IRF5) mRNA expression in liver biopsies from control patients with normal liver (n = 7) and patients with fatty liver (n = 10), nonalcoholic steatohepatitis (NASH; n = 8), and hepatitis C virus infection (HCV; n = 11). (B) IRF5 mRNA expression in the same cohort of patients (n = 36) stratified by fibrosis stage. (C) Representative images of IRF5 (pink stain) and CD68 (brown stain) immunostaining in liver sections from selected patients. Colocalization of stains shown by red arrows. (D) Correlative analyses of IRF5 mRNA expression with plasma aspartate and alanine transaminase (AST and ALT, respectively) levels, bilirubin levels, and prothrombin time from the same cohort of patients (n = 36). Scale bars: 100 μm. Differences between patient groups determined by 1-way ANOVA. Correlative analyses were assessed by Spearman’s test. All values reported as mean ± SEM. ***P < 0.001.

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