Myocardial infarction (MI) triggers a process of tissue repair characterized by inflammation, extensive scarring and fibrosis of the myocardium, and reduced function of the heart. Macrophages have a critical role in ischemic heart repair, performing both pro-healing and detrimental functions. Using single-cell sequencing (scRNA-seq) analysis, we previously described accumulation of monocyte-derived Trem2+Spp1+ pro-fibrotic macrophages enriched in a lipid-associated macrophage signature (LAM), a macrophage signature observed in different fibrosis-associated diseases.

In the present work, we focus on investigating the role of triggering receptor-expressed on myeloid cell 2 (TREM2) in post-MI inflammation and cardiac repair, as TREM2 is known to control LAM macrophage function in different disease contexts.

We used scRNA-seq and spatial transcriptomic to unravel Trem2+Spp1+ macrophages localization and function in a mouse model of myocardial infarction using Trem2-deficient mice. We also investigated which are the factors responsible to induce the pro-fibrotic LAM signature using bone marrow-derived macrophages.

After MI, Trem2-/- mice exhibited reduction of Trem2+Spp1+ pro-fibrotic macrophages infiltration at day 5 after MI. Moreover, myofibroblast area was reduced at day 7 after MI and fibrosis was reduced at day 28 after MI in Trem2-/- mice compared to wild type. Nevertheless, survival and cardiac function were unaffected between Trem2-/- and wild type mice. Bone marrow-derived macrophages challenged with apoptotic neutrophils, but not necrotic cardiomyocytes and activated platelets, showed upregulation of pro-fibrotic genes (Spp1, Timp2, Tgfb1, Mmp14, Fn1, Gdf15).

Overall, our data describe a population of monocyte-derived Trem2+Spp1+ macrophages infiltrating the infarcted heart, conserved across species, and has a role in supporting fibrosis by modulating myofibroblast activation (Fig. 1).