Role and therapeutic targeting of TREM2 in monocyte/macrophage dependent ischemic heart repair

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Ischemic heart disease is the leading cause of death worldwide. Myocardial infarction triggers the loss of non-regenerative cardiac tissue, inciting a wound healing process characterized by the formation of a fibrous scar, and gradual pathological remodeling of the heart leads to the transition to heart failure. Precisely understanding the mechanisms of cardiac repair is required to develop new therapeutic strategies for myocardial infarction patients. The inflammatory response that develops in the heart after ischemic injury is a major determinant of cardiac repair. In particular, circulating monocytes massively infiltrate the heart after infarction, where they differentiate into monocyte-derived macrophages with a dual role in cardiac repair, as they participate in inflammation-induced tissue damage but also perform functions necessary for tissue repair (such as dead cell removal, neovascularization). Thus, it is essential to identify mechanisms that promote monocyte/macrophage tissue repair capacities while taming their pathogenic functions. Recently, we mapped gene expression signatures of monocytes/macrophages in experimental myocardial infarction, and identified expression of the cell surface receptor TREM2 (Triggering Receptor Expressed on Myeloid cells-2) as a marker of monocytes/macrophages with a pro-tissue repair gene expression signature. The TREM2 pathway has been shown to be preferentially activated in macrophages in pathological contexts (e.g. neurodegeneration), attenuates macrophage pro-inflammatory activation, and drives macrophage functions such as phagocytosis or survival. We hypothesize that TREM2 controls monocyte/macrophage protective functions in the ischemic heart, and is a target for therapeutic immune modulation of ischemic heart repair. Using TREM2 deficient and loss-of-function mouse models, we will investigate the role of TREM2 in the monocyte response to myocardial infarction and analyze its role in monocyte production, phenotype and trafficking to the ischemic heart. We will furthermore analyze the role of TREM2 in monocyte differentiation into protective macrophages, and how these macrophages locally interact with other cardiac cell types to drive cardiac repair. Finally, we will test the hypothesis that activation of the TREM2 pathway with an anti-TREM2 activating antibody promotes monocyte/macrophage protective features and ameliorates cardiac repair. This project will provide an in-depth characterization of the role of TREM2 in monocyte/macrophage dependent cardiac repair, and proof of concept that TREM2 constitutes a therapeutic target for immune modulation of ischemic heart repair.