title: Atg7 Knockdown Augments Concanavalin A-Induced Acute Hepatitis through an ROS-Mediated p38/MAPK Pathway.
abstract: Concanavalin A (ConA), a T-cell mitogen that induces acute autoimmune hepatitis, is widely used to model pathophysiological processes of human acute autoimmune liver disease. Although autophagy has been extensively studied in the past decade, little is known about its molecular mechanism underlying the regulation of ConA-induced acute hepatitis. In this study, we used a Cre-conditional atg7 KO mouse to investigate the effects of Atg7-associated autophagy on ConA-induced murine hepatitis. Our results demonstrated that atg7 deficiency in mice enhanced macrophage activation and increased pro-inflammatory cytokines upon ConA stimulation. Atg7 silencing resulted in accumulation of dysfunctional mitochondria, disruption of reactive oxygen species (ROS) degradation, and increase in pro-inflammatory cytokines in Raw264.7 cells. p38/MAPK and NF-κB levels were increased upon ConA induction due to Atg7 deficiency. Blocking ROS production inhibited ConA-induced p38/IκB phosphorylation and subsequent intracellular inflammatory responses. Hence, this study demonstrated that atg7 knockout in mice or Atg7 knockdown in cell culture augmented ConA-induced acute hepatitis and related cellular malfunction, indicating protective effects of Atg7 on regulating mitochondrial ROS via a p38/MAPK-mediated pathway. Collectively, our findings reveal that autophagy may attenuate macrophage-mediated inflammatory response to ConA and may be the potential therapeutic targets for acute liver injury.
authors.affiliation: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Road II, Shanghai 200025, China.|Department of Basic Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, United States of America.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhuang
authors.affiliation: Department of Basic Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, United States of America.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Basic Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, United States of America.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Li
authors.affiliation: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Road II, Shanghai 200025, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Department of Basic Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, United States of America.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000235:genetics* / Q000276:immunology; D000071193:Autophagy-Related Protein 7; D003208:Concanavalin A / Q000633:toxicity; D019693:Hepatitis, Autoimmune / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D006801:Humans; D008099:Liver / Q000276:immunology / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000276:immunology / Q000473:pathology; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics* / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D017382:Reactive Oxygen Species; D003208:Concanavalin A; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes