Macrophages in Atheromatous Plaque Developmental Stages

Abstract

Atherosclerosis is the main pathomechanism leading to cardiovascular diseases such as myocardial infarction or stroke. There is consensus that atherosclerosis is not only a metabolic disorder but rather a chronic inflammatory disease influenced by various immune cells of the innate and adaptive immune system. Macrophages constitute the largest population of inflammatory cells in atherosclerotic lesions. They play a critical role in all stages of atherogenesis. The heterogenous macrophage population can be subdivided on the basis of their origins into resident, yolk sac and fetal liver monocyte-derived macrophages and postnatal monocyte-derived, recruited macrophages. Recent transcriptomic analyses revealed that the major macrophage populations in atherosclerosis include resident, inflammatory and foamy macrophages, representing a more functional classification. The aim of this review is to provide an overview of the trafficking, fate, and functional aspects of the different macrophage populations in the "life cycle" of an atheromatous plaque. Understanding the chronic inflammatory state in atherosclerotic lesions is an important basis for developing new therapeutic approaches to abolish lesion growth and promote plaque regression in addition to general cholesterol lowering.

Keywords: atherosclerosis; fate; macrophage; monocyte; regression; trafficking.

FIGURE 1

Fate, trafficking and functional changes of macrophages during the “life cycle” of an atheromatous (murine) plaque. EMP-derived macrophages seed the tissues between day E9 and E12 of embryonic development. Macrophages reside primarily in the adventitia and sustain through local proliferation. Monocyte-derived macrophages from the fetal liver and, around birth, from the bone marrow seed the vessel wall and differentiate in the adventitia. The recently introduced intima resident macrophages (Mac^AIR) originate from the bone marrow and maintain through local proliferation. They are the first macrophages to get in contact with lipoproteins in the intima and are outnumbered and replaced by newly recruited monocyte-derived macrophages during atherogenesis. At advanced disease stages, local macrophage proliferation dominates cell turnover. Vascular smooth muscle cells may transdifferentiate and adapt a macrophage-like phenotype and contribute to the atheromatous foam cell population. The role of adventitial macrophages in this context remains to be elucidated. Major atheromatous plaque macrophage subpopulations, as defined by their transcriptomes, include resident (Ccl8, Lyve-1, FOLR2, CXCL4, F13a1, Wfdc17), inflammatory (Cxcl2, Ccl2, Ccl3, Ccl4, Il-1b, TNF), and TREM-2⁺ foamy (Lgals3, Cd9, Ctsd) macrophages. The degree of plasticity in between subpopulations and their respective roles in disease progression are under investigation. In murine models of atherosclerotic regression, inflammatory macrophages showed less Nlrp3 and IL1β expression while Trem2^hi foamy macrophages expressed more Mertk and less Mmp2 in line with a rather atheroprotective function.