Institute of Immunology, University of Duisburg-Essen, Essen, Germany.
Institute of Immunology, University of Duisburg-Essen, Essen, Germany.
Cell Rep. 2020 Mar 17;30(11):3671-3681.e5. doi: 10.1016/j.celrep.2020.02.101.
Infections can result in a temporarily restricted unresponsiveness of the innate immune response, thereby limiting pathogen control. Mechanisms of such unresponsiveness are well studied in lipopolysaccharide tolerance; however, whether mechanisms of tolerance limit innate immunity during virus infection remains unknown. Here, we find that infection with the highly cytopathic vesicular stomatitis virus (VSV) leads to innate anergy for several days. Innate anergy is associated with induction of apoptotic cells, which activates the Tyro3, Axl, and Mertk (TAM) receptor Mertk and induces high levels of interleukin-10 (IL-10) and transforming growth factor β (TGF-β). Lack of Mertk in Mertk mice prevents induction of IL-10 and TGF-β, resulting in abrogation of innate anergy. Innate anergy is associated with enhanced VSV replication and poor survival after infection. Mechanistically, Mertk signaling upregulates suppressor of cytokine signaling 1 (SOCS1) and SOCS3. Dexamethasone treatment upregulates Mertk and enhances innate anergy in a Mertk-dependent manner. In conclusion, we identify Mertk as one major regulator of innate tolerance during infection with VSV.
感染可导致先天免疫反应暂时受限，从而限制病原体的控制。脂多糖耐受中的这种无反应性的机制已得到很好的研究；然而，在病毒感染期间，耐受机制是否限制先天免疫仍然未知。在这里，我们发现感染高细胞病变性的水疱性口炎病毒（VSV）可导致先天无反应性持续数天。先天无反应性与凋亡细胞的诱导有关，凋亡细胞激活了 Tyro3、Axl 和 Mertk（TAM）受体 Mertk，并诱导高水平的白细胞介素 10（IL-10）和转化生长因子-β（TGF-β）。在 Mertk 缺失的 Mertk 小鼠中，缺乏 Mertk 可防止诱导 IL-10 和 TGF-β，从而消除先天无反应性。先天无反应性与 VSV 复制增强和感染后存活率降低有关。从机制上讲，Mertk 信号转导上调细胞因子信号转导抑制物 1（SOCS1）和 SOCS3。地塞米松治疗以 Mertk 依赖性方式上调 Mertk 并增强先天无反应性。总之，我们确定 Mertk 是感染 VSV 期间先天耐受的主要调节剂之一。
