Periodontitis aggravates atherosclerosis by inducing inflammatory response and macrophage pyroptosis through the...

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).

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.

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.

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.

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.