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
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 o...
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2025-07-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
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| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.124.041220 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Xiaowen Wu |
| collection | DOAJ |
| description | 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 TREM2 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 FeCl3‐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. |
| format | Article |
| id | doaj-art-3f0a744eb1c14e91811ae2d3f9e37e82 |
| institution | DOAJ |
| issn | 2047-9980 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Wiley |
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| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj-art-3f0a744eb1c14e91811ae2d3f9e37e822025-08-20T03:09:31ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802025-07-01141310.1161/JAHA.124.041220Endoplasmic Reticulum Stress‐Induced triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Downregulation Exacerbates Platelet Activation and Myocardial Infarction in Patients With Coronary Artery DiseaseXiaowen Wu0Guanxing Pan1Lin Chang2Qian Liu3Yangyang Liu4Wei Zhang5Yifan Guo6Ge Zhang7Haoxuan Zhong8Zhiyong Qi9Jianjun Zhang10Ruyi Xue11She Chen12Hu Hu13Jianzeng Dong14Si Zhang15Zhongren Ding16School of Pharmacy Tianjin Medical University Tianjin ChinaDepartment of Biochemistry and Molecular Biology School of Basic Medical Sciences, Fudan University Shanghai ChinaDepartment of Biochemistry and Molecular Biology School of Basic Medical Sciences, Fudan University Shanghai ChinaSchool of Pharmacy Tianjin Medical University Tianjin ChinaDepartment of Cardiology The First Affiliated Hospital of Zhengzhou University Zhengzhou ChinaDepartment of Biochemistry and Molecular Biology School of Basic Medical Sciences, Fudan University Shanghai ChinaDivision of Cardiovascular Disease Zhongshan Hospital, Fudan University Shanghai ChinaDepartment of Biochemistry and Molecular Biology School of Basic Medical Sciences, Fudan University Shanghai ChinaDepartment of Cardiology Huashan Hospital, Fudan University Shanghai ChinaDivision of Cardiovascular Disease Zhongshan Hospital, Fudan University Shanghai ChinaDepartment of Clinical Laboratory Shanghai Pudong Hospital, Fudan University Pudong Medical Center Shanghai ChinaDepartment of Internal Medicine, Institute of Liver Disease Fudan University Zhongshan Hospital Shanghai ChinaDepartment of Biochemistry and Molecular Biology School of Basic Medical Sciences, Fudan University Shanghai ChinaDepartment of Pathology and Pathophysiology Zhejiang University School of Medicine Zhejiang ChinaDepartment of Cardiology The First Affiliated Hospital of Zhengzhou University Zhengzhou ChinaDepartment of Biochemistry and Molecular Biology School of Basic Medical Sciences, Fudan University Shanghai ChinaSchool of Pharmacy Tianjin Medical University Tianjin ChinaBackground 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 TREM2 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 FeCl3‐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.https://www.ahajournals.org/doi/10.1161/JAHA.124.041220coronary artery diseaseER stressplateletTREM2TREM2‐activating antibody |
| spellingShingle | 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 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 Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease coronary artery disease ER stress platelet TREM2 TREM2‐activating antibody |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | coronary artery disease ER stress platelet TREM2 TREM2‐activating antibody |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.124.041220 |
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