Signal Transduction and Targeted Therapy (May 2025)

Porphyromonas gingivalis aggravates atherosclerotic plaque instability by promoting lipid-laden macrophage necroptosis

  • Xiaofei Huang,
  • Mengru Xie,
  • Yixuan Wang,
  • Xiaofeng Lu,
  • Feng Mei,
  • Kaiwen Zhang,
  • Xinlong Yang,
  • Guangjin Chen,
  • Ying Yin,
  • Guangxia Feng,
  • Wencheng Song,
  • Nianguo Dong,
  • Xuliang Deng,
  • Songling Wang,
  • Lili Chen

DOI
https://doi.org/10.1038/s41392-025-02251-6
Journal volume & issue
Vol. 10, no. 1
pp. 1 – 18

Abstract

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Abstract At advanced phases of atherosclerosis, the rupture and thrombogenesis of vulnerable plaques emerge as primary triggers for acute cardiovascular events and fatalities. Pathogenic infection such as periodontitis-associated Porphyromonas gingivalis (Pg) has been suspected of increasing the risks of atherosclerotic cardiovascular disease, but its relationship with atherosclerotic plaque destabilization remains elusive. Here we demonstrated that the level of Pg-positive clusters positively correlated with the ratio of necrotic core area to total atherosclerotic plaque area in human clinical samples, which indicates plaque instability. In rabbits and Apoe −/− mice, Pg promoted atherosclerotic plaque necrosis and aggravated plaque instability by triggering oxidative stress, which led to macrophage necroptosis. This process was accompanied by the decreased protein level of forkhead box O3 (FOXO3) in macrophages. The mechanistic dissection showed that Pg lipopolysaccharide (LPS) evoked macrophage oxidative stress via the TLR4 signaling pathway, which subsequently activated MAPK/ERK-mediated FOXO3 phosphorylation and following degradation. While the gingipains, a class of proteases produced by Pg, could effectively hydrolyze FOXO3 in the cytoplasm of macrophages. Both of them decreased the nuclear level of FOXO3, followed by the release of histone deacetylase 2 (HDAC2) from the macrophage scavenger receptor 1 (Msr1) promoter, thus promoting Msr1 transcription. This enhanced MSR1-mediated lipid uptake further amplified oxidative stress-induced necroptosis in lipid-laden macrophages. In summary, Pg exacerbates macrophage oxidative stress-dependent necroptosis, thus enlarges the atherosclerotic plaque necrotic core and ultimately promotes plaque destabilization.