Polymicrobial sepsis is the result of an exaggerated host immune response to bacterial pathogens. Animal models and human studies demonstrate that acute alcohol intoxication is a key risk factor for sepsis-induced mortality. Multiple chemokines, such as CXCL1, CXCL2 and CXCL5 are critical for neutrophil recruitment and proper function of neutrophils. However, it is not quite clear the mechanisms by which acute alcohol suppresses immune responses and whether alcohol-induced immunosuppression can be rescued by chemokines. Thus, we assessed whether acute ethanol challenge via gavage diminishes antibacterial host defense in a sepsis model using cecal ligation and puncture (CLP) and whether this immunosuppression can be rescued by exogenous CXCL1. We found acute alcohol intoxication augments mortality and enhances bacterial growth in mice following CLP. Ethanol exposure impairs critical antibacterial functions of mouse and human neutrophils including reactive oxygen species production, neutrophil extracellular trap (NET) formation, and NET-mediated killing in response to both Gram-negative (E. coli) and Gram-positive (Staphylococcus aureus) pathogens. As compared with WT (C57Bl/6) mice, CXCL1 knockout mice display early mortality following acute alcohol exposure followed by CLP. Recombinant CXCL1 (rCXCL1) in acute alcohol challenged CLP mice increases survival, enhances bacterial clearance, improves neutrophil recruitment, and enhances NET formation (NETosis). Recombinant CXCL1 (rCXCL1) administration also augments bacterial killing by alcohol-treated and E. coli- and S. aureus-infected neutrophils. Taken together, our data unveils novel mechanisms underlying acute alcohol-induced dysregulation of the immune responses in polymicrobial sepsis, and CXCL1 is a critical mediator to rescue alcohol-induced immune dysregulation in polymicrobial sepsis.

细菌性败血症是宿主对细菌病原体过度免疫反应的结果。动物模型和人体研究表明，急性酒精中毒是败血症诱发的死亡率的关键危险因素。多种趋化因子（例如CXCL1，CXCL2和CXCL5）对于嗜中性粒细胞募集和嗜中性粒细胞的正常功能至关重要。但是，尚不清楚急性酒精抑制免疫反应的机制以及趋化因子是否可以挽救酒精诱导的免疫抑制。因此，我们评估了通过盲肠进行急性乙醇攻击是否会在使用盲肠结扎和穿刺（CLP）的脓毒症模型中降低抗菌宿主防御能力，以及这种免疫抑制是否可以通过外源性CXCL1挽救。我们发现急性酒精中毒可增加CLP后小鼠的死亡率并增强细菌生长。Ë。大肠杆菌）和革兰氏阳性（金黄色葡萄球菌）病原体。与WT（C57Bl / 6）小鼠相比，CXCL1基因敲除小鼠在急性酒精和CLP暴露后表现出早期死亡。急性酒精攻击的CLP小鼠中的重组CXCL1（rCXCL1）可提高存活率，增强细菌清除率，改善中性粒细胞募集并增强NET形成（NETosis）。重组CXCL1（rCXCL1）的给药还可以增强酒精处理和E对细菌的杀灭作用。coli-和小号。金黄色感染的中性粒细胞。综上所述，我们的数据揭示了急性酒精诱导的多菌性脓毒症免疫反应异常调节的新机制，CXCL1是挽救酒精引起的多菌性脓毒症免疫调节异常的关键介质。