The Circadian Clock Controls Immune Checkpoint Pathway in Sepsis.
The Circadian Clock Controls Immune Checkpoint Pathway in Sepsis.
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昼夜节律时钟控制脓毒症中的免疫检查点通路
DOI：
10.1016/j.celrep.2018.06.026
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发表时间：
2018-07-10
期刊：
影响因子：
8.8
通讯作者：
Tang D
中科院分区：
文献类型：
--
作者：
Deng W;Zhu S;Zeng L;Liu J;Kang R;Yang M;Cao L;Wang H;Billiar TR;Jiang J;Xie M;Tang D
脓毒症和脓毒性休克与由宿主对感染的反应受损引起的危及生命的器官功能障碍相关。虽然生物钟紊乱损害了早期炎症反应，但其对脓毒症后免疫抑制的影响仍不清楚。在这里，我们表明，Bmal 1，核心生物钟基因，在实验性脓毒症的宿主免疫反应的调节中发挥作用。从机制上讲，巨噬细胞中的Bmal 1缺陷会增加PKM 2表达和乳酸产生，这是以STAT 1依赖性方式表达免疫检查点蛋白PD-L1所必需的。因此，骨髓细胞中Pkm 2的靶向消融或施用抗PD-L1中和抗体或补充重组白细胞介素-7（IL-7）有助于微生物清除，抑制T细胞凋亡，减少多器官功能障碍，并减少Bmal 1缺陷小鼠的脓毒性死亡。总的来说，这些发现表明，生物钟控制着巨噬细胞中的免疫检查点通路，因此代表了致命感染的潜在治疗靶点。Deng等人证明，BMAL 1通过反调节PD-L1表达和T细胞衰竭在严重感染期间预防脓毒症表型的发展中发挥作用。这些发现表明，靶向生物钟和免疫代谢途径具有治疗导致致命败血症的感染性疾病的潜力。
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. Deng et al. demonstrate that BMAL1 plays a role in preventing the development of a sepsis phenotype during severe infection through counter-regulating PD-L1 expression and T cell exhaustion. These findings indicate that targeting the circadian clock and immunometabolism pathway has potential for treating infectious diseases that lead to lethal sepsis.
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影响因子：
120.7
作者：
Boomer, Jonathan S.;To, Kathleen;Chang, Kathy C.;Takasu, Osamu;Osborne, Dale F.;Walton, Andrew H.;Bricker, Traci L.;Jarman, Stephen D., II;Kreisel, Daniel;Krupnick, Alexander S.;Srivastava, Anil;Swanson, Paul E.;Green, Jonathan M.;Hotchkiss, Richard S.
通讯作者：
Hotchkiss, Richard S.
影响因子：
4.6
作者：
Oishi Y;Hayashi S;Isagawa T;Oshima M;Iwama A;Shimba S;Okamura H;Manabe I
通讯作者：
Manabe I
DOI：
10.1073/pnas.1106750109
发表时间：
2012-01-10
影响因子：
11.1
作者：
Gibbs, Julie E.;Blaikley, John;Loudon, Andrew S. I.
通讯作者：
Loudon, Andrew S. I.
影响因子：
9.8
作者：
Haas R;Smith J;Rocher-Ros V;Nadkarni S;Montero-Melendez T;D'Acquisto F;Bland EJ;Bombardieri M;Pitzalis C;Perretti M;Marelli-Berg FM;Mauro C
通讯作者：
Mauro C
DOI：
10.4049/jimmunol.1001026
发表时间：
2010-11-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Castanon-Cervantes O;Wu M;Ehlen JC;Paul K;Gamble KL;Johnson RL;Besing RC;Menaker M;Gewirtz AT;Davidson AJ
通讯作者：
Davidson AJ