中性粒细胞功能紊乱是脓毒症免疫抑制的重要机制。系统性炎症导致中性粒细胞凋亡延迟而引起非特异脏器损伤；吞噬细菌导致中性粒细胞程序性坏死而降低病菌清除能力。申请人前一自然基金首次发现脓毒症时中性粒细胞表达PD-L1与CD80，PD-L1阳性中性粒细胞出现功能紊乱。预实验显示γ干扰素抑制中性粒细胞自发性凋亡，伴有PD-L1表达上调与p85磷酸化增强，免疫共沉淀等显示PD-L1与CD80可相互结合，且二者均可与p85结合，推测脓毒症时PD-L1与CD80可发生双向应答并通过PI3K调控中性粒细胞存活状态。本课题拟研究脓毒症患者中性粒细胞PD-L1和CD80表达水平与中性粒细胞凋亡、坏死及病情和预后的关系；通过离体实验证实PD-L1和CD80双向应答对中性粒细胞凋亡和程序性坏死的影响和信号机制；最后通过在体实验验证这种应答对脓毒症病情的影响，从而最终为改善中性粒细胞功能状态和脓毒症预后提供新靶点。

Neutrophil dysfunction is one of the main mechanisms of sepsis induced immunosuppression. Systemic inflammation may lead to delayed apoptosis in neutrophils, which then induce nonspecific injury of organs. On the other hand, bacterial phagocytosis may result in necroptosis in neutrophils which lead to impaired capacity of bacterial killing. In the previous study supported by the NSFC, the applicants found, for the first time, that neutrophils expressed PD-L1 and CD80 during sepsis, and the PD-L1-positive neutrophils showed impaired function. Our preliminary studies showed that interferon-γ delayed neutrophil apoptosis, accompanied with upregulation of PD-L1 and p85 phosphorylation. The co-IP showed that PD-L1 interacted with CD80, and both of them can combine with p85. These results suggested that PD-L1 and CD80 might have bi-directional interactions, which regulated neutrophil viability via PI3K pathway. The present study aimed to investigate the correlation of PD-L1 and CD80 expression in neutrophils with neutrophil apoptosis, necroptosis and patient prognosis; the effect and associated signaling pathways of PD-L1/CD80 interactions were investigated in the in vitro studies; finally, the role of such effect on the progression of sepsis was investigated in the in vivo studies, so as to provide a new target for improving neutrophil function and the outcome of sepsis.