Nonalcoholic Steatohepatitis Exacerbates Inflammatory Bone Destruction and Macrophage NLR Family Pyrin Domain-Containing 3 Inflammasome Activation in Ligature-Induced Periodontitis

Metabolic disorders and accompanying complications pose considerable risks to systemic organ health. Clinical studies have revealed a significant correlation between nonalcoholic steatohepatitis (NASH) and increased severity of periodontitis. However, directed mechanistic insights remain limited. This study aimed to elucidate the direct impact of NASH on periodontitis progression and to investigate the underlying mechanisms using both in vivo and in vitro models. In mice, a NASH diet induced severe liver damage and steatosis compared with chow-fed controls. Furthermore, NASH significantly exacerbated ligature-induced periodontitis, as evidenced by enhanced alveolar bone loss, inflammatory infiltration, and osteoclast activity. Notably, NASH was associated with elevated macrophage NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation in periodontitis relative to lean controls. Mechanistic in vitro experiments revealed that metabolic stimuli, palmitic acid and cholesterol, synergistically promoted NLRP3 inflammasome activation in Porphyromonas gingivalis, P. gingivalis lipopolysaccharide, as well as Escherichia coli lipopolysaccharide-conditioned macrophages. Importantly, macrophage conditioned medium generated with the combination of palmitic acid and cholesterol markedly potentiated osteoclast differentiation and function, as evidenced by enhanced osteoclastogenesis, F-actin ring assembly, and bone resorptive activity in receptor activator of NF-κΒ ligand-stimulated bone marrow-derived macrophages. This study suggests that NASH exacerbates experimental periodontitis by priming periodontal macrophages through the metabolic activation of the NLRP3 inflammasome. These collective data uncover a novel mechanism linking systemic metabolic dysregulation and osteoimmune responses, providing important insights into the comorbidity of inflammatory diseases.