The uric acid crystal receptor Clec12A potentiates type I interferon responses

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  • Kai Li, Institut für Klinische Chemie und Pathobiochemie, Technische Universität München, German Center for Infection Research (DZIF), Munich, Tyskland
  • Konstantin Neumann, Institut für Klinische Chemie, Medizinische Hochschule Hannover, Tyskland
  • Vikas Duhan, Institut für Immunologie, Universitätklinikum Essen, Tyskland
  • Sukumar Namineni, Institut für Virologie, Technische Universität München, Tyskland
  • Anne Louise Hansen
  • Tim Wartewig, Institut für Klinische Chemie und Pathobiochemie, Technische Universität München, Tyskland
  • Zsuzsanna Kurgyis, Institut für Klinische Chemie und Pathobiochemie, Technische Universität München, Tyskland
  • Christian Kanstrup Holm
  • Mathias Heikenwalder, Institut für Virologie, Technische Universität München, Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Tyskland
  • Karl S. Lang, Institut für Immunologie, Universitätklinikum Essen, Tyskland
  • Jürgen Ruland, Institut für Klinische Chemie und Pathobiochemie, Technische Universität München, German Center for Infection Research (DZIF), Munich, German Cancer Consortium (DKTK), Heidelberg, Tyskland
The detection of microbes and damaged host cells by the innate immune system is essential for host defense against infection and tissue homeostasis. However, how distinct positive and negative regulatory signals from immune receptors are integrated to tailor specific responses in complex scenarios remains largely undefined. Clec12A is a myeloid cell-expressed inhibitory C-type lectin receptor that can sense cell death under sterile conditions. Clec12A detects uric acid crystals and limits proinflammatory pathways by counteracting the cell-activating spleen tyrosine kinase (Syk). Here, we surprisingly find that Clec12A additionally amplifies type I IFN (IFN-I) responses in vivo and in vitro. Using retinoic acid-inducible gene I (RIG-I) signaling as a model, we demonstrate that monosodium urate (MSU) crystal sensing by Clec12A enhances cytosolic RNA-induced IFN-I production and the subsequent induction of IFN-I–stimulated genes. Mechanistically, Clec12A engages Src kinase to positively regulate the TBK1-IRF3 signaling module. Consistently, Clec12A-deficient mice exhibit reduced IFN-I responses upon lymphocytic choriomeningitis virus (LCMV) infection, which affects the outcomes of these animals in acute and chronic virus infection models. Thus, our results uncover a previously unrecognized connection between an MSU crystal-sensing receptor and the IFN-I response, and they illustrate how the sensing of extracellular damage-associated molecular patterns (DAMPs) can shape the immune response.
OriginalsprogEngelsk
TidsskriftPNAS (Proceedings of the National Academy of Sciences of the United States of America)
Vol/bind116
Nummer37
Sider (fra-til)18544-18549
Antal sider6
ISSN0027-8424
DOI
StatusUdgivet - sep. 2019

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