Department of Anatomy, Hubei Province Key Laboratory of Allergy and Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan 430071, China; Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Microbes Infect. 2024 Jul-Aug;26(5-6):105352. doi: 10.1016/j.micinf.2024.105352. Epub 2024 May 8.
The blockade of programmed death-ligand 1 (PD-L1) pathway has been clinically used in cancer immunotherapy, while its effects on infectious diseases remain elusive. Roles of PD-L1 signaling in the macrophage-mediated innate immune defense against M.tb is unclear. In this study, the outcomes of tuberculosis (TB) in wild-type (WT) mice treated with anti-PD-1/PD-L1 therapy and macrophage-specific Pdl1-knockout (Pdl1) mice were compared. Treatment with anti-PD-L1 or anti-PD-1 benefited protection against M.tb infection in WT mice, while Pdl1 mice exhibited the increased susceptibility to M.tb infection. Mechanistically, the absence of PD-L1 signaling impaired M.tb killing by macrophages. Furthermore, elevated STAT3 activation was found in PD-L1-deficient macrophages, leading to increased interleukin (IL)-6 production and reduced inducible nitric oxide synthase (iNOS) expression. Inhibiting STAT3 phosphorylation partially impeded the increase in IL-6 production and restored iNOS expression in these PD-L1-deficient cells. These findings provide valuable insights into the complexity and mechanisms underlying anti-PD-L1 therapy in the context of tuberculosis.
程序性死亡配体 1（PD-L1）通路的阻断已在癌症免疫治疗中得到临床应用，但其在传染病中的作用仍不清楚。PD-L1 信号在巨噬细胞介导的针对结核分枝杆菌（M.tb）的固有免疫防御中的作用尚不清楚。在这项研究中，比较了抗 PD-1/PD-L1 治疗和巨噬细胞特异性 Pdl1 敲除（Pdl1）小鼠中野生型（WT）小鼠的结核（TB）结局。抗 PD-L1 或抗 PD-1 的治疗有益于 WT 小鼠对 M.tb 感染的保护，而 Pdl1 小鼠则表现出对 M.tb 感染的易感性增加。从机制上讲，PD-L1 信号的缺失损害了巨噬细胞对 M.tb 的杀伤能力。此外，在 PD-L1 缺陷型巨噬细胞中发现 STAT3 激活增加，导致白细胞介素（IL）-6 产生增加和诱导型一氧化氮合酶（iNOS）表达减少。抑制 STAT3 磷酸化部分阻碍了这些 PD-L1 缺陷型细胞中 IL-6 的产生增加，并恢复了 iNOS 的表达。这些发现为抗 PD-L1 治疗在结核病背景下的复杂性和机制提供了有价值的见解。
