Liver transplantation patients are at increased risk for methicillin-resistant Staphylococcus aureus (MRSA) infection, but the molecular mechanism remains unclear. We found that genetic predisposition to low pannexin 1 (PANX1) expression in donor livers was associated with MRSA infection in human liver transplantation recipients. Using Panx1 and Il-33-knockout mice for liver transplantation models with MRSA tail vein injection, we demonstrated that Panx1 deficiency increased MRSA-induced liver injury and animal death. We found that decreased PANX1 expression in the liver led to reduced release of adenosine triphosphate (ATP) from hepatocytes, which further reduced the activation of P2X2, an ATP-activating P2X receptor. Reduced P2X2 function further decreased the NLRP3-mediated release of interleukin-33 (IL-33), reducing hepatic recruitment of macrophages and neutrophils. Administration of mouse IL-33 to Panx1^−/− mice significantly (P = 0.011) ameliorated MRSA infection and animal death. Reduced human hepatic IL-33 protein abundance also associated with increased predisposition to MRSA infection. Our findings reveal that genetic predisposition to reduced PANX1 function increases risk for MRSA infection after liver transplantation by decreasing hepatic host innate immune defense, which can be attenuated by IL-33 treatment.

肝移植患者发生耐甲氧西林金黄色葡萄球菌(MRSA) 感染的风险增加，但其分子机制仍不清楚。我们发现供体肝脏中低 pannexin 1 (PANX1) 表达的遗传易感性与人类肝移植受者的 MRSA 感染有关。使用Panx1和Il-33敲除小鼠进行 MRSA 尾静脉注射的肝移植模型，我们证明了Panx1缺乏会增加 MRSA 引起的肝损伤和动物死亡。我们发现肝脏中 PANX1 表达的降低导致肝细胞中三磷酸腺苷 (ATP) 的释放减少，这进一步降低了 P2X2（一种 ATP 激活的 P2X 受体）的激活。降低的 P2X2 功能进一步降低了 NLRP3 介导的白细胞介素 33 (IL-33) 的释放，从而减少了巨噬细胞和中性粒细胞的肝脏募集。对Panx1 ^-/-小鼠施用小鼠 IL-33显着 ( P= 0.011) 改善 MRSA 感染和动物死亡。人类肝脏 IL-33 蛋白丰度的降低也与 MRSA 感染的易感性增加有关。我们的研究结果表明，降低 PANX1 功能的遗传易感性会通过降低肝脏宿主的先天免疫防御来增加肝移植后 MRSA 感染的风险，这可以通过 IL-33 治疗减弱。