2. Academic Validation
  3. Porphyromonas gingivalis aggravates atherosclerotic plaque instability by promoting lipid-laden macrophage necroptosis

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

  • Signal Transduct Target Ther. 2025 May 23;10(1):171. doi: 10.1038/s41392-025-02251-6.
Xiaofei Huang # 1 2 3,  Mengru Xie # 1 2 3,  Yixuan Wang # 4 5,  Xiaofeng Lu 1 2 3,  Feng Mei 1 2 3,  Kaiwen Zhang 1 2 3,  Xinlong Yang 1 2,  Guangjin Chen 1 2 3,  Ying Yin 1 2 3,  Guangxia Feng 1 2 3,  Wencheng Song 1 2 3,  Nianguo Dong 6 7,  Xuliang Deng 8,  Songling Wang 9 10,  Lili Chen 11 12 13
Affiliations

Affiliations

  • 1 Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China.
  • 4 Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5 Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
  • 6 Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 1986xh0694@hust.edu.cn.
  • 7 Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China. 1986xh0694@hust.edu.cn.
  • 8 Department of Geriatric Dentistry, NMPA Key Laboratory for Dental Materials, National Engineering Laboratory for Digital and Material, Technology of Stomatology, Beijing Laboratory of Biomedical Materials, Peking University School and Hospital of Stomatology, Beijing, China. kqdengxuliang@bjmu.edu.cn.
  • 9 Laboratory of Homeostatic Medicine, School of Medicine, Southern University of Science and Technology, Shenzhen, China. wangsl@sustech.edu.cn.
  • 10 Beijing Laboratory of Oral Health, Capital Medical University, Beijing, China. wangsl@sustech.edu.cn.
  • 11 Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. chenlili1030@hust.edu.cn.
  • 12 School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. chenlili1030@hust.edu.cn.
  • 13 Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China. chenlili1030@hust.edu.cn.
  • # Contributed equally.
PMID: 40404630 DOI: 10.1038/s41392-025-02251-6
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.

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