National Clinical Research Center for Infectious Diseases, Guangdong Provincial Clinical Research Center for Tuberculosis, The Third People's Hospital of Shenzhen, Southern University of Science and Technology, Shenzhen, China.
Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China.
J Immunol. 2022 Jun 1;208(11):2515-2522. doi: 10.4049/jimmunol.2101015. Epub 2022 May 9.
The cannabinoid receptor 2 (CB2) is a receptor mainly expressed in immune cells and believed to be immunosuppressive in infective or inflammatory models. However, its role in sepsis has not been fully elucidated. In this study, we delineate the function and mechanism of CB2 in the cecal ligation and puncture-induced septic model in mice. The activation of CB2 signaling with HU308 led to decreased survival rates and more severe lung injury in septic mice, and lower IL-10 levels in peritoneal lavage fluid were observed in the CB2 agonist group. The mice with conditional knockout of CB2-encoding gene CNR2 in CD4 T cells (CD4 Cre CNR2) improved survival, enhanced IL-10 production, and ameliorated pulmonary damage in the sepsis model after CB2 activation. In addition, double-knockout of the CNR2 gene (Lyz2 Cre CD4 Cre CNR2) decreased the susceptibility to sepsis compared with Lyz2 Cre CNR2 mice. Mechanistically, the blockade of IL-10 with the anti-IL-10 Ab abolished its protection in CD4 Cre CNR2 mice. In accordance with the animal study, in vitro results revealed that the lack of CNR2 in CD4 cells elevated IL-10 production, and CB2 activation inhibited CD4 T cell-derived IL-10 production. Furthermore, in the clinical environment, septic patients expressed enhanced CB2 mRNA levels compared with healthy donors in PBMCs, and their CB2 expression was inversely correlated with IL-10. These results suggested that the activation of CD4 T cell-derived CB2 increased susceptibility to sepsis through inhibiting IL-10 production.
大麻素受体 2 (CB2) 主要表达于免疫细胞，被认为在感染或炎症模型中具有免疫抑制作用。然而，其在脓毒症中的作用尚未完全阐明。在本研究中，我们描绘了 CB2 在盲肠结扎和穿刺诱导的小鼠脓毒症模型中的功能和机制。用 HU308 激活 CB2 信号导致脓毒症小鼠的存活率降低和更严重的肺损伤，并且在 CB2 激动剂组中观察到腹腔灌洗液中的 IL-10 水平降低。在 CD4 T 细胞中条件性敲除 CB2 编码基因 CNR2 的小鼠（CD4 Cre CNR2）在 CB2 激活后改善了脓毒症模型中的存活率、增强了 IL-10 产生并改善了肺损伤。此外，与 Lyz2 Cre CNR2 小鼠相比，CNR2 基因的双重敲除（Lyz2 Cre CD4 Cre CNR2）降低了对脓毒症的易感性。从机制上讲，用抗 IL-10 Ab 阻断 IL-10 消除了其在 CD4 Cre CNR2 小鼠中的保护作用。与动物研究一致，体外结果表明 CD4 细胞中缺乏 CNR2 会增加 IL-10 的产生，而 CB2 激活会抑制 CD4 T 细胞衍生的 IL-10 产生。此外，在临床环境中，与健康供体相比，脓毒症患者 PBMCs 中表达的 CB2 mRNA 水平增强，并且他们的 CB2 表达与 IL-10 呈负相关。这些结果表明，CD4 T 细胞衍生的 CB2 的激活通过抑制 IL-10 产生增加了对脓毒症的易感性。
