BACKGROUND AND AIMS 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. METHODS 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. RESULTS 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. CONCLUSION 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.

中文翻译：

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IL-33/ST2 通路调节中性粒细胞迁移并预测重度酒精性肝炎患者的预后

背景和目的 严重酒精性肝炎 (SAH) 与高感染风险相关。白细胞介素 33 (IL33)/ST2 通路参与败血症控制，但缺乏酒精相关肝病 (ALD) 的数据。我们旨在表征 IL-33/ST2 在 ALD 和 SAH 患者中性粒细胞 (PMN) 中的作用。方法从SAH、酒精性肝硬化(Cirrh)和健康对照(Ctrl)患者中收集血清和循环中性粒细胞。我们量化了基线和暴露于 IL-33 后的 IL-33/ST2 通路和 CXCR2。我们还确定了 PMN 的迁移能力。结果 IL-33 的诱饵受体 (sST2) 在 SAH 与 Cirrh 和 Ctrl 中增加，表明 ALD 期间该途径存在缺陷。sST2 水平与治疗反应、2 个月生存率、SAH 的无感染生存率和感染概率。内毒素血症与 sST2 呈弱相关。GRK2 是 CXCR2 的负调节因子，在 SAH 和 Cirrh PMN 中过度表达，并被 IL-33 降低。与 Cirrh 和 Ctrl 相比，SAH 中 PMN 上的 CXCR2 水平较低。用 IL-33 治疗部分恢复了 SAH 和 Cirrh 中 CXCR2 的表达。与 Ctrl 相比，SAH 和 Cirrh 中 IL-8 的 PMN 迁移较低。用 IL-33 治疗部分恢复了 SAH 和 Cirrh 的迁移。有趣的是，与无反应者相比，皮质类固醇反应者（里尔<0.45）的中性粒细胞迁移能力和对 IL-33 的反应增强。结论 IL33/ST2 通路在 SAH 中存在缺陷并可预测结果。这种缺陷与中性粒细胞表面 CXCR2 表达降低和迁移能力降低有关，这可以通过 IL-33 来纠正，尤其是对类固醇有反应的患者。这些结果表明在 SAH 及其感染并发症中具有治疗潜力。