Periodontitis aggravates atherosclerosis by inducing inflammatory response and macrophage pyroptosis through the NF‐κB/NLRP3/caspase‐1 pathway

BACKGROUND: This study investigates whether periodontitis exacerbates atherosclerosis (AS) by inducing an inflammatory response and macrophage pyroptosis through Porphyromonas gingivalis lipopolysaccharide (P.g.-LPS)-mediated activation of the NF-κB/NLRP3/caspase-1 pathway, aiming to identify potential therapeutic targets linking periodontal inflammation to atherosclerotic cardiovascular disease (ASCVD). METHODS: Apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat diet (HFD) were used as AS models, with periodontitis induced by molar ligation and P. gingivalis application. Plaque levels, serum lipids, serum pro-inflammatory markers, and aortic protein expression were assessed. In vitro, THP-1 macrophages were treated with oxidized low-density lipoprotein (ox-LDL) and/or P.g.-LPS, with or without the NLRP3 inhibitor MCC950. Pyroptosis (LDH release) and pathway activation were analyzed. RESULTS: In vivo, the ApoE(-/-) + HFD + periodontitis group exhibited more severe intimal hyperplasia (adjusted p < 0.05) and upregulated aortic expression of TLR4, NLRP3(the core sensor of the inflammasome), F4/80 (a specific murine macrophage marker), and Gasdermin D (GSDMD) (the executor of pyroptosis) versus ApoE(-/-) + HFD controls (all p < 0.05). In vitro, ox-LDL and P.g.-LPS co-treatment in THP-1 cells synergistically increased LDH and IL-1β release (all adjusted p < 0.05) and maximally induced mRNA/protein levels of the NF-κB/NLRP3/caspase-1/GSDMD axis. Critically, this synergistic effect was abrogated by MCC950, confirming the centrality of NLRP3 inflammasome activation. CONCLUSIONS: Our findings reveal a key mechanistic link between periodontitis and atherosclerosis progression, demonstrating that NF-κB/NLRP3/caspase-1-mediated macrophage pyroptosis serves as a critical pathogenic bridge. These results identify this inflammatory cell-death pathway as a potential focal point for understanding and intervening in the exacerbation of ASCVD by periodontal infection. PLAIN LANGUAGE SUMMARY: This study demonstrates that periodontitis exacerbates atherosclerosis (AS) through in vivo and in vitro models. In ApoE(-/-) mice fed a high-fat diet, periodontitis aggravated aortic plaque formation, elevated pro-inflammatory cytokines, dyslipidemia, and enhanced macrophage pyroptosis compared to AS controls. Mechanistically, Porphyromonas gingivalis lipopolysaccharide (P.g.-LPS) synergized with ox-LDL to activate the NF-κB/NLRP3/caspase-1 pathway in macrophages, driving pyroptosis and amplifying inflammatory responses. This synergistic effect was blocked by the NLRP3 inhibitor MCC950. These findings identify the NF-κB/NLRP3/caspase-1 axis as a pivotal link between periodontal inflammation and AS progression, suggesting that targeting this pathway might represent a potential therapeutic avenue for mitigating atherosclerotic cardiovascular disease (ASCVD) risk associated with periodontal disease.