NLRP3 inflammasome is regulated in osteoclasts through a Tmem178-dependent mechanism that restricts calcium influx

Abstract Osteoclasts (OCs) differentiate from macrophages in response to RANKL. Here, we investigated the role of the NLRP3 inflammasome in mouse macrophages, with or without exposure to RANKL. Unexpectedly, we found that NLRP3 expression gradually declined during osteoclastogenesis but could be restored with LPS treatment. LPS and nigericin robustly activated this inflammasome in macrophages, as expected, but not in OCs. Mechanistically, we identified Tmem178, a protein that restrains Ca 2+ release from the endoplasmic reticulum (ER) and highly expressed in OCs, as an inhibitor of this inflammasome. Notably, NLRP3 inflammasome activation was robust in OCs lacking Tmem178 or wild-type (WT) OCs exposed to high calcium concentrations. In vivo studies demonstrated that under the conditions where OCs efficiently release Ca 2+ from bone, inflammasome formation was enhanced. Furthermore, deletion of Nlrp3 rescued osteopenia in Tmem178 −/− mice. Thus, we found that Tmem178 uniquely restricts Ca 2+ release from ER in OCs, thereby suppressing NLRP3 inflammasome activation. One Sentence Summary The NLRP3 inflammasome is silenced in the OC lineage by Tmem178 to prevent pathological bone loss.