Pyroptosis by caspase11/4‐gasdermin‐D pathway in alcoholic hepatitis in mice and patients

Abstract

These results implicate pyroptosis induced by the CASP11/4-GSDMD pathway in the pathogenesis of AH. (Hepatology 2018;67:1737-1753).

Hepatocytes and neutrophils cooperatively suppress bacterial infection by differentially regulating lipocalin‐2 and neutrophil extracellular traps

“…Cirrhotic liver tissues from different etiologies (e.g., NASH, hepatitis C virus [HCV], autoimmune hepatitis [AH]) and liver tissues from acetaminophen (APAP)–induced liver failure were obtained through the Liver Tissue Procurement and Distribution System (National Institutes of Health contract HHSN276201200017C), University of Minnesota. Severe alcoholic hepatitis (SAH) patient and control human livers were obtained from the Clinical Resources for Alcoholic Hepatitis (1R24AA025017), Johns Hopkins University, as described . All samples were collected by snap‐freezing in liquid nitrogen.…”

“…Severe alcoholic hepatitis (SAH) patient and control human livers were obtained from the Clinical Resources for Alcoholic Hepatitis (1R24AA025017), Johns Hopkins University, as described. (25) All samples were collected by snap-freezing in liquid nitrogen.…”

Inflammasome‐associated cell death: Pyroptosis, apoptosis, and physiological implications

“…124 A previous study demonstrated that the caspase-11/4-GSDMD pathway was activated in the liver during alcoholic hepatitis. 125 In a mouse model of alcoholic hepatitis, a caspase-11 deficiency abolished the ductular reaction, hepatocellular death, and liver bacterial load, which implies that caspase-11 contributes to the pathogenesis of alcoholic liver disease. By contrast, GSDMD may protect against noninfectious liver injury, which is induced by hemorrhagic shock associated with resuscitation or acetaminophen overdose, by regulating apoptosis and necroptosis.…”

Gasdermins and their role in immunity and inflammation

“…GSDMD also contributes to sterile inflammation in liver disease (Khanova et al, 2018; Xu et al, 2018). In a mouse model of alcoholic hepatitis, it was shown that GSDMD and caspase-11 were both activated and that expression of constitutively active GSDMD worsened hepatocellular death and leukocyte inflammation (Khanova et al, 2018).…”

“…GSDMD also contributes to sterile inflammation in liver disease (Khanova et al, 2018; Xu et al, 2018). In a mouse model of alcoholic hepatitis, it was shown that GSDMD and caspase-11 were both activated and that expression of constitutively active GSDMD worsened hepatocellular death and leukocyte inflammation (Khanova et al, 2018). Similarly, samples from nonalcoholic steatohepatitis patients displayed GSDMD-driven pyroptosis and GSDMD deletion–mitigated development of steatohepatitis in mice (Xu et al, 2018).…”