Tissue experienced resident macrophages of the perivascular niche in myocardial infarction – PERIMAC

Resident tissue macrophages (RTM) are essential cellular components of adult tissues regulating homeostasis beyond their classical immune surveillance functions. The heart is an archetypal example of adult tissue with RTM. Cardiac RTM represent around 6% to 8% of the non-cardiomyocyte population in the healthy myocardium and have been implicated in electrical conduction, control of cardiomyocyte mitochondrial metabolism, or development of the arterial and lymphatic vasculature. In cardiac injury models, RTM are anti-fibrotic, promote angiogenesis, and regulate the anti-inflammatory response to injury by interacting with other immune cell types, such as monocytes and T lymphocytes, to drive them towards pro-healing phenotypes. Cardiac RTM are heterogeneous cell population encompassing macrophages developed from yolk-sac derived precursors as well as from fetal liver or bone-marrow derived monocytes. Cardiac RTM heterogeneity is also governed by sub-tissular localization and sub-populations of monocyte-derived RTM establish close contacts with blood vessels displaying an array of functions that are important for both cardiac homeostasis and pathology. This suggests a major role of the cardiac tissue itself in controlling the persistence of macrophages and the recruitment and differentiation of monocytes. However, the precise mechanisms governing these processes remain to be defined. Understanding how RTM interact with the other components of the cardiac tissue to shape macrophage identity and functions is a major challenge. In particular, studying how specific cardiac RTM characteristics are established and maintained will help to reveal to what extent immune cell identities are dictated by the environment, as opposed to by cell-intrinsic qualities of the precursors.
The main hypothesis of the present project is that RTM establishing time-dependent residence in the perivascular niche acquire unchallenged reparative function in the cardiac tissue.
The PERIMAC proposal includes three specific aims:
Aim 1: We will characterize the perivascular identity of RTM in the cardiac tissue and unravel the environmental cues involved in this niche-dependent functional programming. We hypothesize that Vsig4 (V-set and immunoglobulin domain-containing protein 4) expression is an exclusive feature of tissue experienced peri-vascular RTM. We anticipate that both monocyte-derived and self-renewing macrophages contribute to the pool of VSIG4+ RTM. We assume that VSIG4+ RTM identity is driven by type 2 cytokines and mainly dependent on the time of residence in the sub-tissular niche rather than the cell-intrinsic merits of the precursors.
Aim 2: We will assess the role of these perivascular RTM in post-ischemic cardiac repair in mice challenged with surgically-induced myocardial infarction. We expect that VSIG4+ RTM display uncontested reparative function and hamper adverse ventricular remodeling in the ischemic heart.
Aim 3: We will decipher the molecular mechanisms-involved in the perivascular RTM-induced reparative function. As VSIG4 belongs to the complement receptor of the immunoglobulin superfamily, we speculate that complement C3 deposition on apoptotic cells intensifies their efficient ingestion by VSIG4+ RTM favoring inflammation resolution and cardiac repair. We further speculate that the combined expression of VSIG4, with that of additional efferocytic receptors, such as TIMD4, specifically co-express on RTM, coordinates time-resolved functions of cardiac macrophages and intensify the anti-inflammatory and tissue repair program within the infarcted heart.