Diverse roles of macrophages in atherosclerosis: from inflammatory biology to biomarker discovery

Abstract

Cardiovascular disease, a leading cause of mortality in developed countries, is mainly caused by atherosclerosis, a chronic inflammatory disease. Macrophages, which differentiate from monocytes that are recruited from the blood, account for the majority of leukocytes in atherosclerotic plaques. Apoptosis and the suppressed clearance of apoptotic macrophages (efferocytosis) are associated with vulnerable plaques that are prone to rupture, leading to thrombosis. Based on the central functions of macrophages in atherogenesis, cytokines, chemokines, enzymes, or microRNAs related to or produced by macrophages have become important clinical prognostic or diagnostic biomarkers. This paper discusses the impact of monocyte-derived macrophages in early atherogenesis and advanced disease. The role and possible future development of macrophage inflammatory biomarkers are also described.

Figure 1

The roles of M1 and M2 macrophages. Ly6C high monocytes differentiate into M1 type, classically activated macrophages that affect proteolysis and produce antibacterial products. Ly6C low monocytes differentiate into M2 type, alternatively activated macrophages that are involved in wound repair and tissue remodelling. M1 and M2 cells secrete different cytokines that function in efferocytosis and the formation of foam cells.

Figure 2

Signalling pathways in a macrophage involved in atherosclerosis. Pro- and anti-inflammatory factors act on macrophages, leading to activation of downstream scavenger receptors (SRs)/toll-like receptors (TLRs)-NF-κB signalling, endoplasmic reticulum (ER) stress and efflux of cholesterol via ABCA and ABCG transporters.

Figure 3

The fate of macrophages in an early lesion of atherosclerosis. The accumulation of apolipoprotein B-lipoproteins (apoB-LPs) in the matrix beneath the endothelial cell layer leads to the recruitment of monocytes. The cells differentiating into macrophages undergo foam cell formation, leading to apoptosis. Because efferocytosis works efficiently, this lesion does not develop necrotic core. The resolution of the inflammation results in decreased plaque progression.

Figure 4

Cellular interactions with macrophages in an advanced lesion. Foam cells accumulate in the intima and undergo apoptosis that is triggered by cytokines. Efferocytes do not function properly, and apoptotic cells secondarily become necrotic cells, contributing to the formation of a necrotic core. Necrosis of macrophages and SMCs decrease collagen synthesis to diminish the collagen content of the fibrous cap, triggering rupture and thrombosis.

Figure 5

Pro- and anti-inflammatory biomarkers and microRNAs related to macrophages. All of these inflammatory markers and mediators, released at different stages of progression in atherosclerosis, can enter the circulation, affecting the prognosis of patients with atherosclerosis.