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NONCANONICAL PYROPTOSIS PROMOTES NONALCOHOLIC STEATOHEPATITIS VIA LIPID PEROXIDATION AND TRAINED IMMUNITY
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2022
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Biomedical Sciences
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http://dx.doi.org/10.34944/dspace/7631
Abstract
Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of abnormal liver function in countries with western-style high fat, high cholesterol diets. Liver damage associated with NAFLD may lead to liver cirrhosis, end-stage liver disease and hepatocellular carcinoma (HCC). Additionally, recent data suggest that nonalcoholic steatohepatitis (NASH), the inflammatory phase of NAFLD, is linked to increased cardiovascular risk independent of the broad spectrum of risk factors of metabolic syndrome. Therefore, novel therapies are needed to inhibit the inflammatory liver damage that drives NAFLD. Hepatic macrophages (HMΦ’s), which include resident Kupffer cells and monocyte-derived macrophages, are the primary drivers of liver inflammation in both human and mouse models. In macrophages, chronic lipid exposure promotes pro-inflammatory polarization and the activation of pyroptosis via the NLRP3 inflammasome. While the role of the canonical pyroptosis pathway has been studied in NAFLD, the role of the newly discovered noncanonical (caspase-11/-Gasdermin-Ddependent) pathway has not been defined. Diet-induced NAFLD promoted hepatic steatosis and lobular inflammation in male WT mice. Caspase-11 deficiency decreases macrovesicular steatosis and total NAFLD Activity Score (NAS). High fat feeding promoted recruitment and activation of HMΦ in both Caspase-11 deficient (Casp11KO) and WT male mice, however, noncanonical pyroptosis (caspase-11 activity, surface Gasdermin-D, expression, liver IL-1β secretion) was ablated in HMΦs from Casp11KO mice. Bone marrow transplantation restored capacity for noncanonical pyroptosis in Casp11KO mice. RNAseq and microarray analysis revealed that lipid peroxidation and trained immunity mediate noncanonical pyroptosis in diet induced NALFD.
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