TREM2 modulates macrophage pyroptosis and inflammatory responses to ameliorate aortic valve calcification

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.

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.

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.

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.