title: ER Stress-induced Inflammasome Activation Contributes to Hepatic Inflammation and Steatosis.
abstract: Endoplasmic reticulum (ER) stress functions as a protein folding and quality control mechanism to maintain cell homeostasis. Emerging evidence indicates that ER stress is also involved in metabolic and inflammatory diseases. However, the link between ER stress and inflammation remains not well characterized. In this study, we have demonstrated that ER stress-induced inflammasome activation plays a critical role in the pathogenesis of hepatic steatosis. By utilizing genetic and pharmacological agent-induced hepatic steatosis animal models, we found that hepatic steatosis was associated with inflammasome activation and ER stress. Our results show that caspase-1 ablation alleviated liver inflammation and injury. Liver tissues from caspase-1 KO mice had significantly reduced production of IL-1β under ER stress conditions. We also found that ER stress promoted inflammasome activation and IL-1β processing in both hepatocytes and Kupffer cells/macrophages. Moreover, lack of caspase-1 ameliorated cell death or pyropoptosis of hepatocytes induced by ER stress. Taken together, our findings suggest that ER stress-induced inflammasome activation and IL-1β production generate a positive feedback loop to amplify inflammatory response, eventually leading to liver steatosis and injury.
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina (MUSC), Charleston, South Carolina 29425-5040, USA; Hollings Cancer Center, Medical University of South Carolina (MUSC), Charleston, South Carolina 29425, USA.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Immunology and Microbiology, Center for Molecular Medicine & Genetics, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Kezhong
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina (MUSC), Charleston, South Carolina 29425-5040, USA; Hollings Cancer Center, Medical University of South Carolina (MUSC), Charleston, South Carolina 29425, USA.
authors.forename: Zihai
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina (MUSC), Charleston, South Carolina 29425-5040, USA; Hollings Cancer Center, Medical University of South Carolina (MUSC), Charleston, South Carolina 29425, USA.
authors.forename: Beichu
authors.initials: B
authors.lastname: Guo
keywords: Endoplasmic reticulum; Inflammasome; Liver; Steatosis