International immunopharmacology · 2025
TREM2 modulates macrophage pyroptosis and inflammatory responses to ameliorate aortic valve calcification.
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Bian Jin-Hui, Yuan Chun-Ze, Gu Jia-Xi, Lin Wen-Feng, Xiong Jia-Qi, Tang Zhi-Wei, Li Ao, Shao Yong-Feng
Аннотация
BACKGROUND: Calcific aortic valve disease (CAVD) leads to valve thickening and calcification. Valvular interstitial cells (VICs) play a crucial role in valve homeostasis and their differentiation into osteoblast-like cells is influenced by macrophages. Triggering receptor expressed on myeloid cells 2 (TREM2) is involved in lipid metabolism and inflammation, but its role in CAVD remains unclear.
METHODS: We evaluated TREM2 expression in CAVD using public datasets and clinical aortic valve samples. To investigate the impact and underlying mechanisms of macrophage TREM2 on VIC osteogenic differentiation, we utilized a high-fat diet (HFD)-induced ApoE-/- mouse model and a THP-1-VIC transwell co-culture system.
RESULTS: TREM2 expression was significantly elevated in macrophages within calcified aortic valve tissues from CAVD patients, as determined by bioinformatics, flow cytometry, qRT-PCR, western blot, and immunofluorescence. Inhibition of TREM2 in ApoE-/- mice on an HFD exacerbated aortic valve calcification. Mechanistically, TREM2 inhibition activated the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, promoting pyroptosis and the release of inflammatory cytokines. Additionally, TREM2 downregulation led to reduced phosphorylation of Syk/PI3K/AKT, decreased activity of respiratory chain complexes, impaired oxidative phosphorylation (OXPHOS), diminished ATP production, and increased reactive oxygen species (ROS) levels.
CONCLUSION: TREM2 regulates macrophage oxidative phosphorylation, NLRP3 inflammasome activation, pyroptosis, and inflammatory responses through the PI3K/AKT pathway. This underscores TREM2 as a potential therapeutic target for mitigating aortic valve calcification and slowing the progression of CAVD.
METHODS: We evaluated TREM2 expression in CAVD using public datasets and clinical aortic valve samples. To investigate the impact and underlying mechanisms of macrophage TREM2 on VIC osteogenic differentiation, we utilized a high-fat diet (HFD)-induced ApoE-/- mouse model and a THP-1-VIC transwell co-culture system.
RESULTS: TREM2 expression was significantly elevated in macrophages within calcified aortic valve tissues from CAVD patients, as determined by bioinformatics, flow cytometry, qRT-PCR, western blot, and immunofluorescence. Inhibition of TREM2 in ApoE-/- mice on an HFD exacerbated aortic valve calcification. Mechanistically, TREM2 inhibition activated the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, promoting pyroptosis and the release of inflammatory cytokines. Additionally, TREM2 downregulation led to reduced phosphorylation of Syk/PI3K/AKT, decreased activity of respiratory chain complexes, impaired oxidative phosphorylation (OXPHOS), diminished ATP production, and increased reactive oxygen species (ROS) levels.
CONCLUSION: TREM2 regulates macrophage oxidative phosphorylation, NLRP3 inflammasome activation, pyroptosis, and inflammatory responses through the PI3K/AKT pathway. This underscores TREM2 as a potential therapeutic target for mitigating aortic valve calcification and slowing the progression of CAVD.