TREM2⁺ macrophages confers post-infarction cardioprotection by restraining ROS via NLRP3 inflammasome

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.