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Endoplasmic Reticulum Stress-Induced triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Downregulation
Xiaowen Wu1, Guanxing Pan2,3, Lin Chang2
1School of Pharmacy Tianjin Medical University Tianjin China.
Insights
Triggering receptor expressed on myeloid cells 2 (TREM2) links endoplasmic reticulum stress, inflammation, and platelet hyperactivity in coronary artery disease. Activating TREM2 may offer a new therapeutic strategy for this condition.
Area of Science:
- Immunology
- Cardiovascular Biology
- Molecular Medicine
Background:
- Coronary artery disease involves chronic immune-inflammation, endoplasmic reticulum (ER) stress, and platelet hyperactivity.
- The signaling hub connecting these pathological processes in coronary artery disease remains unidentified.
- Triggering receptor expressed on myeloid cells 2 (TREM2), an innate immune receptor, is investigated as a potential linking hub.
Purpose of the Study:
- To investigate the role of TREM2 in integrating ER stress, immune inflammation, and platelet function in coronary artery disease.
- To determine the mechanism by which ER stress affects TREM2 expression in platelets.
- To evaluate TREM2 activation as a potential therapeutic target for coronary artery disease.
Main Methods:
- Assessed TREM2 expression and ER stress in human platelets.
- Utilized luciferase assays, chromatin immunoprecipitation, and electrophoretic mobility shift assays to study TREM2 regulation by ER stress.
- Investigated the functional consequences of TREM2 deficiency and TREM2 activation in preclinical models of thrombosis and myocardial infarction.
Main Results:
- Platelets express TREM2, which is downregulated in patients with coronary artery disease.
- Excessive ER stress reduces TREM2 expression via the CHOP-C/EBPα pathway.
- TREM2 deficiency exacerbates platelet activation, thrombosis, and myocardial infarction, while TREM2 activation demonstrates cardioprotective effects.
Conclusions:
- TREM2 acts as a crucial signaling hub integrating ER stress, immune inflammation, and platelet function.
- Downregulation of TREM2 by ER stress contributes to platelet hyperactivation in coronary artery disease.
- Targeting TREM2 activation presents a promising novel therapeutic strategy for 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 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.
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