Heterogeneity of atherosclerotic plaque macrophage origin, phenotype and functions: Implications for treatment

Abstract

Macrophages are key players in atherosclerotic lesions, regulating the local inflammatory milieu and plaque stability by the secretion of many inflammatory molecules, growth factors and cytokines. Monocytes have long been considered to be the main source of plaque macrophages. However, recent findings provide evidence for proliferation of local macrophages or transdifferentiation from other vascular cells as alternative sources. Recent years of research focused on the further identification and characterisation of macrophage phenotypes and functions. In this review we describe the advances in our understanding of monocyte and macrophage heterogeneity and its implications for specific therapeutic interventions, aiming to reduce the ever growing significant risk of cardiovascular events without any detrimental side effects on the patient's immune response.

Single-cell analysis of fate-mapped macrophages reveals heterogeneity, including stem-like properties, during atherosclerosis progression and regression

“…In addition to confirming the considerable heterogeneity of macrophages in plaques reported by others (e.g., refs. [43][44][45][46], our approach has led to several observations: (i) atherosclerosis progression is associated with differentiation into more distinct macrophage states than during regression; (ii) the spectrum of macrophage activation states in both progressing and regressing plaques has greater complexity than the traditional definition of the M1 and M2 polarization phenotypes; and (iii) there is a cluster of proliferating CX3CR1 + monocytes with a stem cell-like signature in both progressing and regressing plaques.…”

Contribution of Extramedullary Hematopoiesis to Atherosclerosis. The Spleen as a Neglected Hub of Inflammatory Cells

“…Ly-6C hi monocyte subset is thought to differentiate into an inflammatory phenotype (55,80). In advanced atheromata, in contrast to previous views on macrophage proliferation, macrophages can proliferate inside the lesions, through an Scavenger Receptor Class A (SRA)-dependent pathway (71,93,94). Cytokines related to leukopoiesis and monocyte mobilization from BM, like M-CSF, G-CSF, and MCP-1, are produced in an enhanced manner by macrophages carrying Abca1/Abcg1 deletion, supporting the role of the dyslipemia in these processes (25,27,44,95).…”

Heterogeneity and plasticity in healthy and atherosclerotic vasculature explored by single-cell sequencing

“…Polarization of macrophages into the pro-inflammatory M1 macrophage, via lipopolysaccharide or tumor necrosis factor-alpha, vs. the anti-inflammatory M2 macrophage, via interleukin (IL)-4 or IL-10, already shows a distinct phenotypic difference 19 . However, we now know that the range of phenotypes is much more subtle and diverse than M1 vs. M2 and that stimuli and microenvironment are decisive for every subset of macrophages 20–22 . Immune cell heterogeneity is not only restricted to macrophages but also occurs in other immune subsets.…”