Dead Cells Induce Innate Anergy via Mertk after Acute Viral Infection

• Main Authors: Tom Adomati, Lamin B. Cham, Thamer A. Hamdan, Hilal Bhat, Vikas Duhan, Fanghui Li, Murtaza Ali, Elisabeth Lang, Anfei Huang, Eyad Naser, Vishal Khairnar, Sarah-Kim Friedrich, Judith Lang, Justa Friebus-Kardash, Michael Bergerhausen, Maximilian Schiller, Yara Maria Machlah, Florian Lang, Dieter Häussinger, Stanislav Ferencik, Cornelia Hardt, Philipp A. Lang, Karl S. Lang
• Format: Article
• Language: English
• Published: Elsevier 2020-03-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124720302758

Summary: 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. : Adomati et al. show that the cytopathic virus VSV leads to innate immune cell anergy. Innate anergy is associated with apoptotic cells through activation of the TAM receptor Mertk and induction of the cytokines IL-10 and TGF-β.