Driss Ehirchiou, Ilaria Bernabei, Veronique Chobaz, Sonia Nasi, Mariela Castelblanco , Alexander So , Hans Acha-Orbea, Thomas Hugle, Li Zhang, Nathalie Busso
Affiliation(s):
Laboratory Of Rheumatology, CHUV Lausanne
In gout, monosodium urate (MSU) crystals are taken up by macrophages, triggering the activation of the NLRP3 inflammasome and the production of IL-1 β. In this study, we report a specific role of integrin CD11b in inflammasome activation in macrophages stimulated by MSU. We demonstrate that CD11b-deficient mice developed exacerbated gouty arthritis with increased recruitment of leukocytes in the joint and higher IL-1 β levels in the sera. In macrophages, genetic deletion of CD11b induced a shift of macrophage metabolism from oxidative phosphorylation to glycolysis, thus decreasing the generation of ATP and increasing the production of IL-6 and IL-1 β and upon MSU stimulation in vitro. Treating macrophages with a CD11b agonist, LA1, inhibited the release of IL-1 β in vitro and in vivo and attenuated the severity of experimental gouty arthritis. Taken together, our data identified the CD11b integrin as a principal cell membrane receptor that mediates inflammasome activation by MSU crystal in macrophages, which could be a potential therapeutic target to treat gouty arthritis in human patients.