The uric acid crystal receptor Clec12A potentiates type I interferon responses

Abstract

Significance Viral infections are accompanied by the release of pathogen-associated molecular patterns (PAMPs) during the virus life-cycle and damage-associated molecular patterns (DAMPs) from collateral injured cells. The sensing of viral PAMPs by pattern recognition receptors (PRRs) such as Toll-like receptors RIG-I and cGAS is essential in initiating host antiviral responses, especially the type I interferon (IFN-I) response. Here, we report that the DAMP-sensing C-type lectin receptor Clec12A positively regulates the IFN-I response induced by RIG-I, providing a mechanism of cross-talk between PAMP- and DAMP-triggered signaling pathways. Moreover, this modulatory function of Clec12A has functional consequences in both acute and chronic viral infection in mice. 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.