SIRPα Cleavage Is Associated with Inflammatory Response, Corticosteroid Nonresponse, and Worse Prognosis in Clinical and Preclinical Models of Alcohol-Associated Hepatitis.

Severe alcohol-associated hepatitis (sAH) has been associated with a high 30-day mortality rate. Corticosteroids are used in patients with sAH with limitations. There are no biomarkers measured upon hospitalization that predict responsiveness to corticosteroids. The role of signal regulatory protein (SIRP)-α, a receptor that regulates inflammation, has not been studied in patients with AH. In prospective test and validation cohorts of sAH patients treated with corticosteroids, plasma cytokines and SIRPα levels were measured. Studies in Sirpa-/- mice and in vitro studies were performed to characterize the impact of Sirpa-/- and cleavage. Plasma SIRPα levels were elevated at baseline in corticosteroid nonresponders (CS-NR) versus responders (CS-R) in both cohorts. Plasma SIRPα levels were elevated with disease severity and mortality. In CS-NR patients, proinflammatory cytokines were increased. In mice, Sirpα cleavage was induced by ethanol and lipopolysaccharide and associated with A disintegrin and metalloproteinase domain-containing protein (Adam)-10 activity and cytokine release. Adam10 inhibition reduced Sirpα cleavage and cytokine release. In an experimental model of alcohol-associated liver disease, Sirpa-/- mice developed exacerbated liver injury and inflammation. Based on these findings, plasma SIRPα is a potential biomarker for responsiveness to corticosteroids and prognosis. Sirpa-/- mice developed a hyperinflammatory phenotype similar to SIRPα cleavage in humans. Future clinical studies are necessary to validate plasma SIRPα as a biomarker to guide the use of corticosteroids in patients with sAH.