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Soluble TREM2 Drives Atherosclerosis via HSP90β-Dependent Myeloid Inflammation
Xiaoqing Guo1, Xiaoming Liu2, Jie Yu2
1Department of Neurology (X.G., M.Q., S.W., J.C., D.J., Y.F., Jiangnan Yu, L.M.), Huazhong University of Science and Technology, Wuhan, China.
Circulation Research
|July 29, 2026
Summary
Soluble TREM2 (sTREM2) exacerbates atherosclerosis by activating the NF-κB pathway via HSP90β. Targeting the sTREM2/HSP90β interaction with 3-bromopyruvate shows therapeutic potential for atherosclerosis.
Area of Science:
- Cardiovascular Research
- Immunology
- Molecular Biology
Background:
- Chronic inflammation drives atherosclerotic cardiovascular disease.
- Anti-inflammatory therapies reduce cardiac events.
- Soluble TREM2 (sTREM2) is elevated in atherosclerosis patients.
Purpose of the Study:
- Investigate the pathological role of sTREM2 in atherosclerosis progression.
- Elucidate the underlying mechanistic pathways of sTREM2.
- Propose targeted therapeutic interventions for sTREM2.
Main Methods:
- Measured plasma sTREM2 levels in human patients and Apoe-/- mice.
- Administered recombinant sTREM2 to Apoe-/- mice.
- Utilized macrophage-specific Hsp90ab1 knockout mice.
- Investigated mechanisms via immunoprecipitation-mass spectrometry.
- Identified antagonists using surface plasmon resonance imaging.
Main Results:
- Plasma sTREM2 levels correlated with atherosclerotic burden.
- Exogenous sTREM2 worsened plaque progression in mice.
- sTREM2 binds HSP90β, activating the IKKs/NF-κB pathway.
- This pathway promotes monocyte adhesion and macrophage activation.
- 3-bromopyruvate disrupted sTREM2/HSP90β interaction and reduced atherosclerosis.
Conclusions:
- sTREM2 promotes myeloid recruitment and macrophage activation via HSP90β-dependent NF-κB signaling.
- The sTREM2/HSP90β axis is a druggable target for atherosclerosis.
- 3-bromopyruvate demonstrates translational potential for atherosclerosis therapy.
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