title: IRF5 governs liver macrophage activation that promotes hepatic fibrosis in mice and humans.
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.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 1138, Sorbonne Universités, UPMC Université Paris 06; Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot; and Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Fawaz
authors.initials: F
authors.lastname: Alzaid
authors.affiliation: INSERM UMRS 1149 and Department of Pathology Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, Clichy, France.
authors.forename: Floriane
authors.initials: F
authors.lastname: Lagadec
authors.affiliation: INSERM UMRS 1149 and Department of Pathology Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, Clichy, France.
authors.forename: Miguel
authors.initials: M
authors.lastname: Albuquerque
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 1138, Sorbonne Universités, UPMC Université Paris 06; Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot; and Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Raphaëlle
authors.initials: R
authors.lastname: Ballaire
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 1138, Sorbonne Universités, UPMC Université Paris 06; Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot; and Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Orliaguet
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 1138, Sorbonne Universités, UPMC Université Paris 06; Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot; and Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hainault
authors.affiliation: École normale supérieure, PSL Research University, Centre National de la Recherche Scientifique (CNRS), INSERM, Institut de Biologie de l'École Normale Supérieure (IBENS), Plateforme Génomique, Paris, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Blugeon
authors.affiliation: École normale supérieure, PSL Research University, Centre National de la Recherche Scientifique (CNRS), INSERM, Institut de Biologie de l'École Normale Supérieure (IBENS), Plateforme Génomique, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lemoine
authors.affiliation: INSERM UMRS 1016, Institut Cochin, Paris, France; CNRS UMR_S 8104, Paris, France; and Laboratoire d'Excellence INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Lehuen
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom.
authors.forename: David G
authors.initials: DG
authors.lastname: Saliba
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom.
authors.forename: Irina A
authors.initials: IA
authors.lastname: Udalova
authors.affiliation: INSERM UMRS 1149 and Department of Pathology Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, Clichy, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Paradis
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 1138, Sorbonne Universités, UPMC Université Paris 06; Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot; and Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Foufelle
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 1138, Sorbonne Universités, UPMC Université Paris 06; Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot; and Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Venteclef
mesh_terms: D000818:Animals; D017209:Apoptosis; D001663:Bilirubin / Q000097:blood; D005260:Female; D022781:Hepatocytes / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000473:pathology*; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism; D000637:Transaminases / Q000097:blood
chemical_list: C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; C498178:Irf5 protein, mouse; D000637:Transaminases; D001663:Bilirubin