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
Year: 2025
Type: article
Abstract: BACKGROUND: Coronary 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. METHODS: -induced mesenteric arterial thrombosis, and myocardial infarction were explored. A TREM2-activating antibody was also evaluated for its antiplatelet, antithrombotic, and cardioprotective potential against myocardial infarction. RESULTS: We 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. CONCLUSIONS: TREM2 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.
Authors: Xiaowen Wu, Guanxing Pan, Lin Chang, Qian Liu, Yangyang Liu, Wei Zhang, Yifan Guo, Ge Zhang, Haoxuan Zhong, Zhiyong Qi, Jianjun Zhang, Ruyi Xue, She Chen, Hu Hu, Jianzeng Dong, Si Zhang, Zhongren Ding
Institutions: Tianjin Medical University, Fujian Medical University, Shanghai Medical College of Fudan University, Fudan University, First Affiliated Hospital of Fujian Medical University, First Affiliated Hospital of Zhengzhou University, Zhongshan Hospital, Huashan Hospital, Pudong Medical Center, Zhejiang University, Tianjin Medical University General Hospital
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,810
OpenAlex ID: W4411550316