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的暂时受限的无反应性，从而限制了病原体的控制。在脂多糖耐受性方面已经充分研究了这种无反应性的机制。但是，耐受机制是否会限制病毒感染过程中的先天免疫力仍然未知。在这里，我们发现高度细胞病性水疱性口炎病毒（VSV）感染会导致先天性无力几天。先天性无能与凋亡细胞的诱导有关，后者激活Tyro3，Axl和Mertk（TAM）受体Mertk，并诱导高水平的白介素10（IL-10）和转化生长因子β（TGF-β）。Mertk中缺少Mertk ^-/-小鼠可防止IL-10和TGF-β的诱导，从而消除先天性无能。先天性无反应与增强的VSV复制和感染后存活率低有关。从机制上讲，Mertk信号上调细胞因子信号1（SOCS1）和SOCS3的抑制因子。地塞米松治疗以依赖于Mertk的方式上调Mertk并增强先天性无反应。总之，我们确定Mertk是VSV感染期间先天耐受的主要调节剂。