title: Macrophage autophagy protects against liver fibrosis in mice.
abstract: Autophagy is a lysosomal degradation pathway of cellular components that displays antiinflammatory properties in macrophages. Macrophages are critically involved in chronic liver injury by releasing mediators that promote hepatocyte apoptosis, contribute to inflammatory cell recruitment and activation of hepatic fibrogenic cells. Here, we investigated whether macrophage autophagy may protect against chronic liver injury. Experiments were performed in mice with mutations in the autophagy gene Atg5 in the myeloid lineage (Atg5(fl/fl) LysM-Cre mice, referred to as atg5(-/-)) and their wild-type (Atg5(fl/fl), referred to as WT) littermates. Liver fibrosis was induced by repeated intraperitoneal injection of carbon tetrachloride. In vitro studies were performed in cultures or co-cultures of peritoneal macrophages with hepatic myofibroblasts. As compared to WT littermates, atg5(-/-) mice exposed to chronic carbon tetrachloride administration displayed higher hepatic levels of IL1A and IL1B and enhanced inflammatory cell recruitment associated with exacerbated liver injury. In addition, atg5(-/-) mice were more susceptible to liver fibrosis, as shown by enhanced matrix and fibrogenic cell accumulation. Macrophages from atg5(-/-) mice secreted higher levels of reactive oxygen species (ROS)-induced IL1A and IL1B. Moreover, hepatic myofibroblasts exposed to the conditioned medium of macrophages from atg5(-/-) mice showed increased profibrogenic gene expression; this effect was blunted when neutralizing IL1A and IL1B in the conditioned medium of atg5(-/-) macrophages. Finally, administration of recombinant IL1RN (interleukin 1 receptor antagonist) to carbon tetrachloride-exposed atg5(-/-) mice blunted liver injury and fibrosis, identifying IL1A/B as central mediators in the deleterious effects of macrophage autophagy invalidation. These results uncover macrophage autophagy as a novel antiinflammatory pathway regulating liver fibrosis.
authors.affiliation: a INSERM U955; Institut Mondor de Recherche Biomédicale ; Créteil ; France.
authors.forename: Jasper
authors.initials: J
authors.lastname: Lodder
authors.forename: Timothé
authors.initials: T
authors.lastname: Denaës
authors.forename: Marie-Noële
authors.initials: MN
authors.lastname: Chobert
authors.forename: JingHong
authors.initials: J
authors.lastname: Wan
authors.forename: Jamel
authors.initials: J
authors.lastname: El-Benna
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Pawlotsky
authors.forename: Sophie
authors.initials: S
authors.lastname: Lotersztajn
authors.forename: Fatima
authors.initials: F
authors.lastname: Teixeira-Clerc
mesh_terms: D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D002251:Carbon Tetrachloride / Q000737:chemistry; D019070:Cell Lineage; D017077:Culture Media, Conditioned; D004195:Disease Models, Animal; D007249:Inflammation / Q000378:metabolism; D053582:Interleukin-1alpha / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007728:Kupffer Cells / Q000166:cytology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000473:pathology*; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D058628:Myofibroblasts / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D017077:Culture Media, Conditioned; C587672:IL1B protein, mouse; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D002251:Carbon Tetrachloride
keywords: Kupffer cell; inflammation; interleukin-1; liver injury; myofibroblast