Macrophages heterogeneity in atherosclerosis - implications for therapy

Abstract

Atherosclerosis is a chronic inflammatory disease occurring within the artery wall and is an underlying cause of cardiovascular complications, including myocardial infarction, stroke and peripheral vascular disease. Its pathogenesis involves many immune cell types with a well accepted role for monocyte/macrophages. Cholesterol-loaded macrophages are a characteristic feature of plaques and are major players in all stages of plaque development. As well as modulating lipid metabolism, macrophages secrete inflammatory cytokines, chemokines and reactive oxygen and nitrogen species that drive pathogenesis. They also produce proteases and tissue factor that contribute to plaque rupture and thrombosis. Macrophages are however heterogeneous cells and when appropriately activated, they phagocytose cytotoxic lipoproteins, clear apoptotic bodies, secrete anti-inflammatory cytokines and synthesize matrix repair proteins that stabilize vulnerable plaques. Pharmacological modulation of macrophage activity therefore represents a potential therapeutic strategy for atherosclerosis. The aim of this review is to provide an overview of the current understanding of the different macrophage subsets and their monocyte precursors, and, the implications of these subsets for atherosclerosis. This will present a foundation for highlighting novel opportunities to exploit the heterogeneity of macrophages as important diagnostic and therapeutic targets for atherosclerosis and its associated diseases.

Fig 1

Activation of macrophages in developing and advanced human atherosclerotic plaques. Monocytes (CD14⁺⁺CD16⁻ or CD16⁺ subsets) enter the developing atheroma guided by adhesion molecules and chemokines and once infiltrated can differentiate into macrophages, dendritic cells or osteoclasts. Differences in monocyte subsets also exist for mice (see text for details). In response to microenvironmental stimuli, macrophages become activated to develop either atherogenic or atheroprotective functions. The factors controlling entry of the different monocyte subsets into plaque and whether specific monocyte subsets differentiate into distinct functional macrophage subsets requires further investigation. M1 macrophages are microbicidal and involved in host defence. They are pro-inflammatory and cause tissue injury and promote lesion development as well as enhancing plaque vulnerability. M2a macrophages are involved in tissue repair. They are anti-inflammatory and can stabilize vulnerable plaques. M2b (e.g. immune complex/LPS activated) and M2c macrophages, as well as macrophages that take up apoptotic cells in the presence of pro-inflammatory stimuli, are immunoregulatory and anti-inflammatory and stabilize or even regress atherosclerotic plaques, see text for further details. Abbreviations: IFN-γ, interferon-γ; LPS, lipopolysaccharide; LDL, low-density lipoprotein; FA fatty acid; t-PA, tissue plasminogen activator; PPAR-γ, peroxisome proliferator activated receptor-gamma; PGE2, prostaglandin-2.