Activation of the NLRP3 inflammasome in osteoclasts is suppressed by a Tmem178-dependent mechanism that restricts Ca2+ influx

Abstract

Activation of the NLRP3 inflammasome can drive bone resorption by osteoclasts in various inflammatory conditions. Here, we identified Tmem178, a protein that restrains Ca²⁺ fluxes by limiting SOCE activation, as an inhibitor of NLRP3 inflammasome activation and the bone-resorbing activity of osteoclasts. We found that NLRP3 abundance gradually decreased during osteoclastogenesis but was restored by treatment with the bacterial product LPS. LPS and the NLRP3 activator nigericin stimulated this inflammasome in macrophages, as expected, but not in osteoclasts or their lineage-committed precursors. This differential NLRP3 activation was due to Tmem178, a protein abundant in osteoclasts that suppressed NLRP3 inflammasome nucleation. Accordingly, NLRP3 inflammasome activation was robust in osteoclasts lacking Tmem178 or in wild-type osteoclasts exposed to high Ca²⁺ concentrations. In vivo studies demonstrated that inflammasome formation was enhanced under conditions in which osteoclasts efficiently release Ca²⁺ from bone and that deletion of Nlrp3 rescued the osteopenic phenotype characteristic of Tmem178^−/− mice. Thus, our results indicate that Tmem178 potently restricts Ca²⁺ influx in osteoclasts, thereby suppressing NLRP3 inflammasome activation.