Dead Cells Induce Innate Anergy Via Mertk after Acute Viral Infection

Abstract

Infections can result in a temporarily restricted unresponsiveness of the innate immune response, and this restriction limits pathogen control. Lipopolysaccharide (LPS) tolerance is the best studied mechanism of such unresponsiveness, however whether mechanisms of tolerance limit innate immunity during virus infection remains unknown. Here we found that infection with the highly cytopathic vesicular stomatitis virus (VSV) leads to innate anergy for several days after infection. Innate anergy was associated with the induction of apoptotic cells which activated the TAM receptor Mertk and induced high levels of IL-10 and TGF-β. Lack of Mertk in Mertk–/– mice prevented the induction of IL-10 and TGF-β resulting in abrogation of innate anergy. Innate anergy was associated with enhanced VSV replication and poor survival after infection. Mechanistically Mertk-signaling upregulated SOCS1 and SOCS3. Dexamethasone treatment which upregulated Mertk enhanced innate anergy in wild-type but not in Mertk-deficient mice. In conclusion we found that Mertk is one major regulator of innate tolerance during infection with VSV.