Abstract
Periodontitis is characterized by periodontal pocket formation, loss of attachment, and alveolar bone resorption. Both innate and adaptive immunity are involved in the pathogenesis of this oral chronic inflammatory disease. Accumulating evidence indicates a critical role of leptin in periodontal diseases. However, the mechanism by which leptin promotes periodontitis pathogenesis remains unclear. In the present study, we observed an elevated expression of leptin in the serum of periodontitis mice compared to that in healthy controls. There was a higher extent of M1 phenotype macrophage infiltration in mice periodontitis samples than in healthy controls. A positive correlation was observed between the serum leptin levels and M1 macrophages. Treatment with leptin increased M1 macrophage polarization and decreased M2 macrophage polarization in RAW 264.7 cells. Moreover, leptin facilitated lipopolysaccharide (LPS)–induced M1 phenotype macrophage polarization in RAW 264.7 cells. In bone marrow–derived macrophages (BMDMs) generated from leptin-deficient obese (ob/ob) mice, M1 macrophage polarization was significantly attenuated after LPS stimulation compared to the healthy controls. With regards to the molecular mechanism, we found that leptin activated the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and promoted M1 polarization via the NLRP3 inflammasome in vitro. In BMDMs generated from Nlrp3–/– mice, M1 macrophage polarization was significantly attenuated after synchronous stimulation with leptin and LPS compared with BMDMs produced by healthy controls. The NLRP3 inhibitor MCC950 also prevented leptin-mediated M1 macrophage polarization in RAW 264.7 cells. Nlrp3–/– periodontitis models indicated that leptin aggravates the periodontal response to the ligature by promoting M1 macrophage polarization via the NLRP3 inflammasome. Taken together, we show that leptin promotes the progression of periodontitis via proinflammatory M1 macrophage skewing, and targeting leptin/NLRP3 signaling may be a feasible approach for treating periodontitis.
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