Deposition of urate and pyrophosphate crystals (MSU and CPP) in the joints are responsible for gout and chondrocalcinosis respectively. The inflammatory reactions induced in these pathologies are due to the activation of resident macrophages involved in the release cytokines including IL1?. The maturation of IL1? is mediated by a multiprotein complex, the NLRP3 inflammasome. We have found that the activation of NLRP3 by crystals depends on cell volume regulation. The LRRC8 family of proteins form the main molecular components of the volume-dependent channel involved in volume regulation. We have found in cultured macrophages that LRRC8 played an essential role in the activation of the inflammasome NRLP3 and the secretion of IL1? following crystal exposure (MSU/CPP). At the same time, we observed in murine inflammatory models that the modulation of osmotic pressure influences the inflammatory processes (IL1?) induced by crystal injection (inhibition by increasing osmotic pressure). We hypothesize that LRRC8 channels control crystal-induced NLRP3 activation through the coincidence of different processes: intracellular Cl- / K + variation, modulation of oxidative stress, and release of extracellular ATP (likely to initiate purinergic action. auto / para-crine, signalling loop). In this project, we will assess i) the role of the LRRC8 / VRAC channel in the activation of NLRP3, IL1? secretion and cell volume in response to crystals, ii) the effect of conditional gene inactivation of LRRC8 in a murine model of crystal inflammation (CR3CR1 / LRRC8A mice) and iii) the involvement of these mechanisms and of LRRC8/VRAC in patients suffering from these pathologies (collection of synovial fluids) in order to identify new therapeutic targets. Altogether, we expect to characterize novel and unexpected functions of the chloride channels LRRC8/VRAC with clear pathophysiological relevance in the context of crystal-induced inflammation.