The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation of Guangdong Higher Education Institutes, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510510, China; Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation of Guangdong Higher Education Institutes, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510510, China.
Cell Rep. 2018 Jul 10;24(2):366-378. doi: 10.1016/j.celrep.2018.06.026.
Sepsis and septic shock are associated with life-threatening organ dysfunction caused by an impaired host response to infections. Although circadian clock disturbance impairs the early inflammatory response, its impact on post-septic immunosuppression remains poorly elucidated. Here, we show that Bmal1, a core circadian clock gene, plays a role in the regulation of host immune responses in experimental sepsis. Mechanistically, Bmal1 deficiency in macrophages increases PKM2 expression and lactate production, which is required for expression of the immune checkpoint protein PD-L1 in a STAT1-dependent manner. Consequently, targeted ablation of Pkm2 in myeloid cells or administration of anti-PD-L1-neutralizing antibody or supplementation with recombinant interleukin-7 (IL-7) facilitates microbial clearance, inhibits T cell apoptosis, reduces multiple organ dysfunction, and reduces septic death in Bmal1-deficient mice. Collectively, these findings suggest that the circadian clock controls the immune checkpoint pathway in macrophages and therefore represents a potential therapeutic target for lethal infection.
脓毒症和感染性休克与宿主对感染的反应受损导致危及生命的器官功能障碍有关。虽然昼夜节律紊乱会损害早期炎症反应，但它对感染后免疫抑制的影响仍不清楚。在这里，我们表明，核心生物钟基因 Bmal1 在实验性脓毒症中宿主免疫反应的调节中发挥作用。从机制上讲，巨噬细胞中 Bmal1 的缺失会增加 PKM2 的表达和乳酸的产生，这对于 PD-L1 免疫检查点蛋白以 STAT1 依赖的方式表达是必需的。因此，靶向敲除髓样细胞中的 Pkm2 或给予抗 PD-L1 中和抗体或补充重组白细胞介素 7 (IL-7) 有助于清除微生物、抑制 T 细胞凋亡、减少多器官功能障碍，并降低 Bmal1 缺陷型小鼠的感染性休克死亡率。总的来说，这些发现表明昼夜节律控制巨噬细胞中的免疫检查点途径，因此代表了治疗致命感染的潜在治疗靶点。
