Department of General Intensive Care Unit, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
Trauma Research Center, Fourth Medical Center of the Chinese PLA General Hospital, Beijing, People's Republic of China.
J Infect Dis. 2020 Oct 1;222(9):1517-1530. doi: 10.1093/infdis/jiaa258.
CD4+CD25+ regulatory T cells (Tregs) play an essential role in sepsis-induced immunosuppression. How, the effects of interleukin 36 (IL-36) cytokines on CD4+CD25+ Tregs and their underlying mechanism(s) in sepsis remain unknown.
Our study was designed to investigate the impacts of IL-36 cytokines on murine CD4+CD25+ Tregs in presence of lipopolysaccharide (LPS) and in a mouse model of sepsis induced by cecal ligation and puncture (CLP). IL-36-activated autophagy was evaluated by autophagy markers, autophagosome formation, and autophagic flux.
IL-36α, IL-36β, and IL-36γ were expressed in murine CD4+CD25+ Tregs. Stimulation of CD4+CD25+ Tregs with LPS markedly up-regulated the expression of these cytokines, particularly IL-36β. IL-36β strongly suppressed CD4+CD25+ Tregs under LPS stimulation and in septic mice challenged with CLP, resulting in the amplification of T-helper 1 response and the proliferation of effector T cells. Mechanistic studies revealed that IL-36β triggered autophagy of CD4+CD25+ Tregs. These effects were significantly attenuated in the presence of the autophagy inhibitor 3-methyladenine or Beclin1 knockdown. In addition, early IL-36β administration reduced the mortality rate in mice subjected to CLP. Depletion of CD4+CD25+ Tregs before the onset of sepsis obviously abrogated IL-36β-mediated protection against sepsis.
These findings suggest that IL-36β diminishes the immunosuppressive activity of CD4+CD25+ Tregs by activating the autophagic process, thereby contributing to improvement of the host immune response and prognosis in sepsis.
CD4+CD25+调节性 T 细胞（Tregs）在脓毒症引起的免疫抑制中发挥重要作用。白细胞介素 36（IL-36）细胞因子对 CD4+CD25+Tregs 的影响及其在脓毒症中的潜在机制尚不清楚。
本研究旨在探讨 IL-36 细胞因子在脂多糖（LPS）存在下对小鼠 CD4+CD25+Tregs 的影响，并在盲肠结扎穿孔（CLP）诱导的脓毒症小鼠模型中进行研究。通过自噬标志物、自噬体形成和自噬流评估 IL-36 激活的自噬。
IL-36α、IL-36β 和 IL-36γ 在小鼠 CD4+CD25+Tregs 中表达。LPS 刺激 CD4+CD25+Tregs 可显著上调这些细胞因子的表达，特别是 IL-36β。IL-36β 在 LPS 刺激下强烈抑制 CD4+CD25+Tregs，并在接受 CLP 挑战的脓毒症小鼠中，导致 T 辅助 1 反应扩增和效应 T 细胞增殖。机制研究表明，IL-36β 触发 CD4+CD25+Tregs 的自噬。在自噬抑制剂 3-甲基腺嘌呤或 Beclin1 敲低存在的情况下，这些作用明显减弱。此外，早期给予 IL-36β 可降低接受 CLP 的小鼠的死亡率。在脓毒症发作前耗尽 CD4+CD25+Tregs 可明显阻断 IL-36β 介导的对脓毒症的保护作用。
这些发现表明，IL-36β 通过激活自噬过程来降低 CD4+CD25+Tregs 的免疫抑制活性，从而有助于改善脓毒症宿主的免疫反应和预后。
