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Pyroptosis, A novel player for alcoholic hepatitis?

Alcoholic hepatitis (AH) is a clinical syndrome of jaundice and liver failure that develops over decades of excessive alcohol consumption, which represents 0.2% of all hospital admissions in the United States. Patients with a severe episode of AH have a potential for 30%-40% 1-month mortality. Recommended treatments for AH include corticosteroids, nutritional supplements, and pentoxifylline. However, these treatments provide only limited survival benefit. One of the main obstacles to developing effective therapeutic drugs to treat AH is the lack of understanding of the molecular mechanisms involved in the pathogenesis of AH. Difficulties in reproducing the histological and clinical features of AH in animal models represent a major limitation in advancing our knowledge of the pathogenesis of AH. Recently, Dr. Hidekazu Tsukamoto’s group developed a hybrid feeding mouse model, which combined ad libitum Western diet feeding with an intragastric ethanol diet, two risk factors for AH. This hybrid feeding mouse model can lead to severe chronic alcoholic steatohepatitis in mice. When a weekly binge was added to this model without changing the total alcohol intake, key histological and clinical changes of AH were reproduced. Hepatocyte death after alcohol consumption is known to contribute to the pathogenesis of alcoholic liver disease. Several types of cell death, including apoptosis, necrosis, and necroptosis, have been observed in cultured hepatocytes and livers of rodents exposed to alcohol as well as in livers of alcoholic liver disease patients. In this issue of HEPATOLOGY, Khanova et al. provide perspectives of a novel cell death named “pyroptosis” in the pathogenesis of AH. Pyroptosis is a type of programmed necrosis that was long thought to depend on the activation of caspase-1, a proinflammatory caspase that is activated by inflammasome complexes. Pyroptosis has been considered an important innate immune response to certain bacterial insults. Pyroptosis is associated with cell swelling and disruption of the plasma membrane due to the formation of pores on the plasma membrane. In addition to caspase-1, caspase-11 (mouse) and caspase-4/5 (human) can sense intracellular lipopolysaccharide to trigger pyroptosis. Mechanistically, activated caspase-11 or caspase-4/5 cleaves gasdermin D (GSDMD) within its linking loop to release its autoinhibition on its GSDMD-N domain. The cleaved GSDMD-N domain binds to phosphoinositides on the plasma membrane and lyses it to cause cell death. GSDMD is expressed in many other tissues and cell types, but it is predominantly expressed in the gastrointestinal tract and immune cells. GSDMD belongs to the gasdermin family of proteins, which has more than five different members in humans. All of them share a similar structure, with the most conserved gasdermin-N domain and gasdermin-C domain. All of the gasdermin proteins have similar pore-forming activity, and thus, pyroptosis is now considered a gasderminmediated program necrosis. In searching for the molecular mediators for the pathogenesis AH, Khanova et al. first performed a global unbiased RNA-sequencing and proteomic analyses in their newly established hybrid feeding mouse AH model and AH patients. Through ontology and pathway analysis, a group of genes involved in the pathway activated by bacterial infection were consistently identified from the mouse AH model and Abbreviations: AAV, adeno-associated virus; AH, alcoholic hepatitis; GSDMD, gasdermin D; IL-1, interleukin-1; KO, knockout; Ttr, transthyretin.