ArticleJournal of the American Heart Association2025
Endoplasmic Reticulum Stress-Induced triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Downregulation Exacerbates Platelet Activation and Myocardial Infarction in Patients With Coronary Artery Disease.
Article in Journal of the American Heart Association, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Atherosclerotic Cell Fates: A Single-Cell View of ER Stress.Journal of cardiovascular development and disease · 2026Review
- Qiliqiangxin capsule attenuates platelet activation and thrombosis by suppressing CaThrombosis journal · 2026Article
- The TREM2 paradox in fibrosis: a unified mechanism for opposite outcomes across organs.Frontiers in immunology · 2026Review
- Glial-mediated immune modulation in glaucomatous neurodegeneration: mechanisms and therapeutic implications.Frontiers in immunology · 2025Review
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Authors and funding
17 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundCoronary artery disease is characterized by chronic immune-inflammation, excessive endoplasmic reticulum (ER) stress, and platelet hyperactivity; however, whether there is a signaling hub linking these events remains unclear. Here, we identified that TREM2 (triggering receptor expressed on myeloid cells 2), an important pattern recognition receptor of the innate immune system, may serve as one such hub.
methodsTREM2 expression and ER stress were assessed in platelets. Transcriptional repression of TREM2 by excessive ER stress was evaluated using luciferase assay, chromatin immunoprecipitation, and electrophoretic mobility shift assay. The effects of TREM2 deficiency on platelet function, mouse FeCl
resultsWe found that platelets express TREM2, and its expression is reduced in platelets from patients with coronary artery disease. Excessive ER stress downregulated TREM2 through the CHOP (C/EBP-homologous protein)-C/EBPα axis. TREM2 deficiency enhanced platelet activation in response to adenosine diphosphate, collagen, and CRP (collagen-related peptide). TREM2 deficiency exacerbated mouse mesenteric arterial thrombosis and aggravated experimental myocardial infarction. Furthermore, a TREM2-activating antibody inhibited platelet activation, reduced thrombosis, and alleviated experimental myocardial infarction. Mechanistically, the TREM2/DAP12 (DNAX activating protein of 12 kDa)/SHIP1 (Src homology 2 domain-containing inositol 5-phosphatase) axis negatively regulated platelet activation through reducing phosphatidylinositol (3,4,5)-trisphosphate levels and inhibiting Akt phosphorylation. Sphingosine-1-phosphate was identified as a physiological TREM2 agonist.
conclusionsTREM2 integrates ER stress, immune inflammation, and platelet function. ER stress-induced TREM2 downregulation contributes to platelet hyperactivation in coronary artery disease, suggesting TREM2 activation as a novel therapeutic target.
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