Ontogeny of arterial macrophages defines their functions in homeostasis and inflammation

Abstract

Arterial macrophages have different developmental origins, but the association of macrophage ontogeny with their phenotypes and functions in adulthood is still unclear. Here, we combine macrophage fate-mapping analysis with single-cell RNA sequencing to establish their cellular identity during homeostasis, and in response to angiotensin-II (AngII)-induced arterial inflammation. Yolk sac erythro-myeloid progenitors (EMP) contribute substantially to adventitial macrophages and give rise to a defined cluster of resident immune cells with homeostatic functions that is stable in adult mice, but declines in numbers during ageing and is not replenished by bone marrow (BM)-derived macrophages. In response to AngII inflammation, increase in adventitial macrophages is driven by recruitment of BM monocytes, while EMP-derived macrophages proliferate locally and provide a distinct transcriptional response that is linked to tissue regeneration. Our findings thus contribute to the understanding of macrophage heterogeneity, and associate macrophage ontogeny with distinct functions in health and disease.

Inhibition of macrophage proliferation dominates plaque regression in response to cholesterol lowering

“…Multiple processes determine macrophage accumulation in the plaque, including monocyte recruitment and differentiation, macrophage proliferation, death and egress [32]. Macrophages of prenatal origin reside in the adventitia and self-sustain through proliferation into adulthood largely independent of monocyte recruitment [15,65]. Whether these embryonically derived macrophages in the adventitia directly contribute to macrophages accumulating in intimal lesions is unknown.…”

Monocyte/Macrophage Lineage Cells From Fetal Erythromyeloid Progenitors Orchestrate Bone Remodeling and Repair

“…Analysis of the expression profiles of eYFP-negative bone marrow-derived and eYFP-positive EMP-derived macrophages in the postnatal tissue of Rank-Cre; Rosa26eYFP mice showed that macrophages from eYFP-positive EMPs expressed high levels of Lyve-1, Stab1, and Gas6, which have been related to homeostatic and anti-inflammatory immune functions. On the other hand, eYFP-negative HSC-derived macrophages characterizes higher expression of Ccr2, which is a marker of HSCs-derived monocyte/macrophage ( Weinberger et al, 2020 ). Use of these markers may be useful in future research to understand the contributions of these populations in homeostasis, tissue repair, and pathology.…”

Vascular Macrophages as Therapeutic Targets to Treat Intracranial Aneurysms

“…A very brief and simplistic overview of M1/M2 biology is represented in Figure 1. However, there is a considerable heterogeneity in macrophage phenotypes and several subtypes have been described such as M1, M2a, M2b, M2c, M2d, Mhem, Mox, M4 (37)(38)(39)(40). This over simplistic representation of M1 as proinflammatory and M2 as anti-inflammatory macrophages is considered here to recognize different functional states of these polarized phenotypes to assign pro-inflammatory and antiinflammatory role.…”

“…Taken together, there are multiple strategies at the level of inflammation and macrophage modulation that have translational potential in human disease. However, the heterogeneity and the complexity of macrophageal response should be cautiously considered in future studies aiming at characterizing the role of these main sentinel cells of ICAs inflammation ( 39 , 40 ). A recent study revealed that during Ang-II induced inflammation of the aorta, primarily adventitial macrophage population expanded due to the infiltration of the bone marrow derived macrophages, whereas the residential embryonic macrophages do show local proliferation, but retain their homeostatic roles ( 40 ).…”

“…However, the heterogeneity and the complexity of macrophageal response should be cautiously considered in future studies aiming at characterizing the role of these main sentinel cells of ICAs inflammation ( 39 , 40 ). A recent study revealed that during Ang-II induced inflammation of the aorta, primarily adventitial macrophage population expanded due to the infiltration of the bone marrow derived macrophages, whereas the residential embryonic macrophages do show local proliferation, but retain their homeostatic roles ( 40 ). Similar, studies utilizing fate mapping, mass cytometry, single cell transcriptomics and proteomics may be required to unveil the complexity and heterogeneity of ICAs macrophages, which may be helpful to design better therapeutic strategies.…”