Soluble TREM2 Drives Atherosclerosis via HSP90β-Dependent Myeloid Inflammation

BACKGROUND: Chronic inflammation is a key driver of atherosclerotic cardiovascular disease. Notably, anti-inflammatory therapies have demonstrated efficacy in reducing cardiac events. We previously reported that TREM2 (triggering receptor expressed on myeloid cells 2) promotes foam cell formation in atherosclerosis. Elevated levels of sTREM2 (soluble TREM2) have been observed in the plasma of patients with atherosclerosis. This study sought to investigate the pathological role of sTREM2 in the progression of atherosclerosis, elucidate its underlying mechanistic pathways, and propose potential targeted therapeutic interventions. METHODS: Plasma sTREM2 levels were measured in patients with carotid atherosclerosis and in apolipoprotein E–deficient ( Apoe −/− ) mice. To study the functional role of sTREM2, we administered recombinant sTREM2 to Apoe −/− mice and used macrophage-specific Hsp90ab1 knockout mice ( Hsp90ab1 Mac-KO ). Mechanistic pathways were investigated using immunoprecipitation-mass spectrometry, and surface plasmon resonance imaging was used to identify sTREM2 antagonists. RESULTS: Plasma sTREM2 levels correlated with atherosclerotic burden in both humans and mice. Exogenous sTREM2 administration exacerbated plaque progression in Apoe −/− mice, an effect abolished in Hsp90ab1 Mac-KO mice. Mechanistically, sTREM2 binds to HSP90β (heat shock protein 90 beta), enhancing its interaction with the IKKs (IκB kinase complex), thereby activating the IκBα (inhibitor of nuclear factor-κB)/NF-κB (nuclear factor-κB) P65 pathway. This activation potentiates monocyte adhesion and chemotaxis and enhances macrophage inflammatory activation signatures in atherosclerotic lesions—effects that were reversed on myeloid-specific Hsp90ab1 deletion. Additionally, we identified 3-bromopyruvate as a small-molecule antagonist that selectively disrupts the sTREM2/HSP90β interaction and attenuates atherosclerosis. CONCLUSIONS: sTREM2 promotes proatherogenic myeloid recruitment and macrophage inflammatory activation via HSP90β-dependent NF-κB activation. Genetic and pharmacological approaches establish the sTREM2/HSP90β axis as a druggable target, with 3-bromopyruvate demonstrating translational potential for atherosclerosis therapy.