Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany; Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.
Applied Systems Biology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute (HKI), Jena, Germany.
Mol Ther. 2021 Jan 6;29(1):338-346. doi: 10.1016/j.ymthe.2020.09.008. Epub 2020 Sep 5.
Complement factor C5a was originally identified as a powerful promoter of inflammation through activation of the C5a receptor 1 (C5ar1). Recent evidence suggests involvement of C5a not only in pro- but also in anti-inflammatory signaling. The present study aims to unveil the role of C5ar1 as potential therapeutic target in a murine sepsis model. Our study discloses a significantly increased survival in models of mild to moderate but not severe sepsis of C5ar1-deficient mice. The decreased mortality of C5ar1-deficient mice is accompanied by improved pathogen clearance and largely preserved liver function. C5ar1-deficient mice exhibited a significantly increased production of the pro-inflammatory mediator interferon-γ (IFN-γ) and a decreased production of the anti-inflammatory cytokine interleukin-10 (IL-10). Together, these data uncover C5a signaling as a mediator of immunosuppressive processes during sepsis and describe the C5ar1 and related changes of the IFN-γ to IL-10 ratio as markers for the immunological (dys)function accompanying sepsis.
补体因子 C5a 最初被鉴定为通过激活 C5a 受体 1（C5ar1）来强力促进炎症反应。最近的证据表明，C5a 不仅参与促炎信号，还参与抗炎信号。本研究旨在揭示 C5ar1 在小鼠脓毒症模型中作为潜在治疗靶点的作用。我们的研究揭示了 C5ar1 缺失小鼠在轻度至中度而非重度脓毒症模型中的存活率显著增加。C5ar1 缺失小鼠的死亡率降低伴随着病原体清除率的提高和肝功能的大量保留。C5ar1 缺失小鼠表现出促炎介质干扰素-γ（IFN-γ）的产生显著增加，抗炎细胞因子白细胞介素-10（IL-10）的产生减少。总之，这些数据揭示了 C5a 信号在脓毒症期间作为免疫抑制过程的介质，并描述了 C5ar1 和相关的 IFN-γ 与 IL-10 比值的变化作为伴随脓毒症的免疫（功能障碍）的标志物。
