Dead Cells Induce Innate Anergy via Mertk after Acute Viral Infection
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
Affiliations
Tom Adomati
Institute of Immunology, University of Duisburg-Essen, Essen, Germany; Corresponding author
Lamin B. Cham
Institute of Immunology, University of Duisburg-Essen, Essen, Germany
Thamer A. Hamdan
Institute of Immunology, University of Duisburg-Essen, Essen, Germany
Hilal Bhat
Institute of Immunology, University of Duisburg-Essen, Essen, Germany
Vikas Duhan
Institute of Immunology, University of Duisburg-Essen, Essen, Germany; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
Fanghui Li
Institute of Immunology, University of Duisburg-Essen, Essen, Germany
Murtaza Ali
Institute of Immunology, University of Duisburg-Essen, Essen, Germany
Elisabeth Lang
University Psychiatric Clinics Basel, Basel, Switzerland
Anfei Huang
Institute of Molecular Medicine, Heinrich Heine University, Düsseldorf, Germany
Eyad Naser
Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany
Vishal Khairnar
Institute of Immunology, University of Duisburg-Essen, Essen, Germany; Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, CA, USA
Sarah-Kim Friedrich
Institute of Immunology, University of Duisburg-Essen, Essen, Germany
Judith Lang
Institute of Immunology, University of Duisburg-Essen, Essen, Germany
Justa Friebus-Kardash
Institute of Immunology, University of Duisburg-Essen, Essen, Germany
Michael Bergerhausen
Institute of Immunology, University of Duisburg-Essen, Essen, Germany
Maximilian Schiller
Institute of Immunology, University of Duisburg-Essen, Essen, Germany
Yara Maria Machlah
Institute of Immunology, University of Duisburg-Essen, Essen, Germany
Florian Lang
Department of Physiology I, Eberhard Karls University of Tübingen, Tübingen, Germany
Dieter Häussinger
Clinic of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University, Düsseldorf, Germany
Stanislav Ferencik
Institute of Immunology, University of Duisburg-Essen, Essen, Germany
Cornelia Hardt
Institute of Immunology, University of Duisburg-Essen, Essen, Germany
Philipp A. Lang
Institute of Molecular Medicine, Heinrich Heine University, Düsseldorf, Germany
Karl S. Lang
Institute of Immunology, University of Duisburg-Essen, Essen, Germany; Corresponding author
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.
