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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,9,10]]},"abstract":"<jats:p>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\u2013stimulated 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.<\/jats:p>","DOI":"10.1073\/pnas.1821351116","type":"journal-article","created":{"date-parts":[[2019,8,26]],"date-time":"2019-08-26T20:55:41Z","timestamp":1566852941000},"page":"18544-18549","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":49,"title":["The uric acid crystal receptor Clec12A potentiates type I interferon responses"],"prefix":"10.1073","volume":"116","author":[{"given":"Kai","family":"Li","sequence":"first","affiliation":[{"name":"Institut f\u00fcr Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universit\u00e4t M\u00fcnchen, 81675 Munich, Germany;"},{"name":"German Center for Infection Research (DZIF), Partner Site Munich, 81675 Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantin","family":"Neumann","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Klinische Chemie, Medizinische Hochschule Hannover, 30625 Hannover, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6337-8225","authenticated-orcid":false,"given":"Vikas","family":"Duhan","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Immunologie, Universit\u00e4tsklinikum Essen, Universit\u00e4t Duisburg\u2013Essen, 45147 Essen, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sukumar","family":"Namineni","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Virologie, Technische Universit\u00e4t M\u00fcnchen\/Helmholtz Zentrum M\u00fcnchen, 81675 Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne Louise","family":"Hansen","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Wartewig","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universit\u00e4t M\u00fcnchen, 81675 Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsuzsanna","family":"Kurgyis","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universit\u00e4t M\u00fcnchen, 81675 Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian K.","family":"Holm","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Heikenwalder","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Virologie, Technische Universit\u00e4t M\u00fcnchen\/Helmholtz Zentrum M\u00fcnchen, 81675 Munich, Germany;"},{"name":"Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl S.","family":"Lang","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Immunologie, Universit\u00e4tsklinikum Essen, Universit\u00e4t Duisburg\u2013Essen, 45147 Essen, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Ruland","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universit\u00e4t M\u00fcnchen, 81675 Munich, Germany;"},{"name":"German Center for Infection Research (DZIF), Partner Site Munich, 81675 Munich, Germany;"},{"name":"German Cancer Consortium (DKTK), 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2019,8,26]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/ni.2845","article-title":"A role for the ITAM signaling module in specifying cytokine-receptor functions","volume":"15","author":"Bezbradica J. 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