IL-33/ST2 pathway regulates neutrophil migration and predicts outcome in patients with severe alcoholic hepatitis.

Severe alcoholic hepatitis (SAH) is associated with a high risk of infection. The interleukin-33 (IL33)/ST2 pathway is involved in sepsis control but data in alcohol-related liver disease (ALD) are lacking. We aimed to characterize the role of IL-33/ST2 in the neutrophils (PMNs) of patients with ALD and SAH.Serum and circulating neutrophils were collected from patients with SAH, alcoholic cirrhosis (Cirrh) and healthy controls (Ctrl). We quantified the IL-33/ST2 pathway and CXCR2 at baseline and after exposure to IL-33. We also determined the migration capacity of PMN.The decoy receptor of IL-33 (sST2) was increased in SAH vs. Cirrh and Ctrl, demonstrating the defect in this pathway during ALD. The sST2 level was associated with response to treatment, 2-month survival, infection-free survival and probability of infection in SAH. Endotoxemia was weakly correlated with sST2. GRK2, a negative regulator of CXCR2, was overexpressed in SAH and Cirrh PMNs and was decreased by IL-33. CXCR2 levels on PMNs were lower in SAH vs. Cirrh and Ctrl. Treatment with IL-33 partially restored CXCR2 expression in SAH and Cirrh. PMN migration upon IL-8 was lower in SAH and Cirrh vs. Ctrl. Treatment with IL-33 partially restored migration in SAH and Cirrh. Interestingly, the migration capacity of PMNs and the response to IL-33 were enhanced in responders to corticosteroids (Lille<0.45) compared to non-responders.The IL33/ST2 pathway is defective in SAH and predicts outcome. This defect is associated with decreased CXCR2 expression on the surface of PMNs and lower migration capacity, which can be corrected by IL-33, especially in patients responding to steroids. These results suggest a therapeutic potential in SAH and its infectious complications.