OBJECTIVES: NLRP3 inflammasome is a critical part of the innate immune system and plays an important role in a variety of inflammatory diseases. However, the effects of NLRP3 inflammasome on periodontitis have not been fully studied. MATERIALS AND METHODS: We used ligature-induced periodontitis models of NLRP3 knockout mice (NLRP3 ) and their wildtype (WT) littermates to compare their alveolar bone phenotypes. We further used Lysm-Cre/Rosa mouse to trace the changes of Lysm-Cre osteoclast precursors in ligature-induced periodontitis with or without MCC950 treatment. At last, we explored MCC950 as a potential drug for the treatment of periodontitis in vivo and in vitro. RESULTS: Here, we showed that the number of osteoclast precursors, osteoclast differentiation and alveolar bone loss were reduced in NLRP3 mice compared with WT littermates, by using ligature-induced periodontitis model. Next, MCC950, a specific inhibitor of the NLRP3 inflammasome, was used to inhibit osteoclast precursors differentiation into osteoclast. Further, we used Lysm-Cre/Rosa mice to demonstrate that MCC950 decreases the number of Lysm-Cre osteoclast precursors in ligature-induced periodontitis. At last, treatment with MCC950 significantly suppressed alveolar bone loss with reduced IL-1β activation and osteoclast differentiation in ligature-induced periodontitis. CONCLUSION: Our findings reveal that NLRP3 regulates alveolar bone loss in ligature-induced periodontitis by promoting osteoclastic differentiation.