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Updated: May 14, 2026
Isolation of Macrophage Subsets and Stromal Cells from Human and Mouse Myocardial Specimens
Published on: December 17, 2019
TREM2+ macrophages confers post-infarction cardioprotection by restraining ROS via NLRP3 inflammasome
Wudi Li1, Sheng-An Su1, Yuan Zhu1
1Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; State Key Laboratory of Transvascular Implantation Devices, Hangzhou 310009, China; Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Hangzhou 310009, China; Transvascular Implantation Devices Research Institute, Hangzhou 310053, China; Binjiang Institute of Zhejiang University, Hangzhou 310053, China.
Abstract:
Maladaptive ventricular remodeling following myocardial infarction (MI) is governed by a dysregulated inflammatory-reparative sequence. Macrophages are central driver in cardiomyocyte death and cardiac fibrosis through mediating inflammatory responses. Triggering receptor expressed on myeloid cells 2 (TREM2), a transmembrane glycoprotein selectively expressed by tissue-resident macrophages, has merged as a critical immune checkpoint. However, its cell-autonomous role in post-MI cardiac remodeling remains unclear. By applying permanent left-anterior-descending coronary ligation in WT mice and TREM2-knockout (TREM2 KO) mice, we found that TREM2 expression was rapidly upregulated in cardiac macrophages at day 7 post-MI, coinciding with the transition from inflammatory to reparative phase. TREM2 KO mice exhibited preserved baseline cardiac function but developed larger infarcts, lower ejection fraction, and higher mortality after MI. Mechanistically, TREM2 deficiency promoted macrophages towards a pro-inflammatory M1 phenotype, amplified the generation of reactive oxygen species (ROS) and activation of the NOD-, LRR- and pyrin domain-containing protein 3(NLRP3) inflammasome in vitro. Additionally, a transwell co-culture model of bone marrow-derived macrophages (BMDMs) and primary mouse cardiomyocytes revealed that TREM2 suppressed cardiomyocyte apoptosis via ROS-NLRP3 signaling. The ROS scavenger N-acetylcysteine (NAC) markedly inhibited inflammatory factor production in TREM2 deficient macrophages and attenuate cardiomyocyte apoptosis. TREM2 functions as a macrophage-intrinsic checkpoint that coordinates the initiation, escalation, and resolution of post-MI inflammation by restraining ROS-NLRP3 signaling. Augmenting TREM2 activity or supplementing soluble TREM2 may represent a novel immunomodulatory strategy to limit adverse remodeling and improve outcomes after MI.
Insights
Triggering receptor expressed on myeloid cells 2 (TREM2) restrains inflammation after heart attack. Lacking TREM2 worsens heart damage and survival by increasing reactive oxygen species and inflammasome activation. Boosting TREM2 may improve outcomes post-myocardial infarction.
Area of Science:
- Immunology
- Cardiovascular Biology
- Cellular and Molecular Medicine
Background:
- Maladaptive ventricular remodeling post-myocardial infarction (MI) involves dysregulated inflammatory and reparative processes.
- Macrophages are key mediators of cardiomyocyte death and cardiac fibrosis following MI.
- Triggering receptor expressed on myeloid cells 2 (TREM2) is a critical immune checkpoint on macrophages, but its role in post-MI remodeling is unclear.
Purpose of the Study:
- To elucidate the cell-autonomous role of TREM2 in cardiac remodeling after myocardial infarction.
- To investigate the mechanisms by which TREM2 influences macrophage phenotype and inflammatory signaling post-MI.
Main Methods:
- Utilized permanent left-anterior-descending coronary ligation in wild-type (WT) and TREM2-knockout (TREM2 KO) mice.
- Analyzed cardiac macrophage phenotype, inflammatory markers, reactive oxygen species (ROS), and NLRP3 inflammasome activation.
- Employed in vitro co-culture systems of bone marrow-derived macrophages (BMDMs) and primary cardiomyocytes, with and without ROS scavenger N-acetylcysteine (NAC).
Main Results:
- TREM2 expression was upregulated in cardiac macrophages post-MI, correlating with the inflammatory-to-reparative phase transition.
- TREM2 KO mice showed exacerbated cardiac dysfunction, larger infarcts, reduced ejection fraction, and increased mortality post-MI.
- TREM2 deficiency promoted a pro-inflammatory M1 macrophage phenotype, amplified ROS generation, and activated the NLRP3 inflammasome, leading to increased cardiomyocyte apoptosis.
Conclusions:
- TREM2 acts as a macrophage-intrinsic checkpoint, regulating the inflammatory response post-MI by restraining ROS-NLRP3 signaling.
- TREM2 deficiency exacerbates adverse cardiac remodeling and outcomes by promoting inflammation and cardiomyocyte death.
- Enhancing TREM2 activity or supplementing soluble TREM2 presents a potential immunomodulatory therapeutic strategy for myocardial infarction.