BACKGROUND: Periodontitis (PD) is a chronic infectious and inflammatory disease characterized by alveolar bone loss. The distinctive activity of immune cells critically exacerbates bone resorption in PD. Myeloid-derived suppressor cells (MDSCs) are known to contribute to various chronic inflammatory conditions, but their role in the pathogenesis and progression of PD remains poorly understood. METHODS: We used single-cell transcriptomic analysis with human gingival samples and animal models of experimental periodontitis to examine the role of M-MDSCs in PD. We also explored the therapeutic effect of depleting MDSCs on PD in vivo. Additionally, the mechanisms of long non-coding RNA Neat1 and the pathway of NF-κB-dependent "canonical NLRP3 inflammasome activation" in MDSCs were investigated in PD. RESULTS: In this study, we revealed that monocytic (M)-MDSCs were significantly increased in inflamed gingiva of PD patients compared to healthy individuals. Expansion of M-MDSCs was also observed in the mouse model of ligature-induced periodontitis, and depletion of MDSCs in PD mice could ameliorate alveolar bone loss and reduce periodontal inflammation. Mechanistically, we found that long non-coding RNA Neat1 was significantly upregulated in M-MDSCs, which achieved this proinflammatory effect by activating NF-κB signaling in PD. Furthermore, the pathway of NF-κB-dependent "canonical NLRP3 inflammasome activation" was confirmed in the PD mouse model, accompanied by increased secretion of proinflammatory cytokines that drive alveolar bone loss, including IL-1β, IL-6 and TNF-α. CONCLUSIONS: In conclusion, this study highlights the pivotal proinflammatory role of M-MDSCs in PD and suggests that targeting these cells may represent a novel immunotherapeutic approach. Future research could focus on strategies to specifically target MDSCs for the treatment of periodontitis.