Macrophage Heterogeneity and Plasticity: Impact of Macrophage Biomarkers on Atherosclerosis

Abstract

Cardiovascular disease (CVD) is a global epidemic, currently representing the worldwide leading cause of morbidity and mortality. Atherosclerosis is the fundamental pathophysiologic component of CVD, where the immune system plays an essential role. Monocytes and macrophages are key mediators in this aspect: due to their heterogeneity and plasticity, these cells may act as either pro- or anti-inflammatory mediators. Indeed, monocytes may develop heterogeneous functional phenotypes depending on the predominating pro- or anti-inflammatory microenvironment within the lesion, resulting in classic, intermediate, and non-classic monocytes, each with strikingly differing features. Similarly, macrophages may also adopt heterogeneous profiles being mainly M1 and M2, the former showing a proinflammatory profile while the latter demonstrates anti-inflammatory traits; they are further subdivided in several subtypes with more specialized functions. Furthermore, macrophages may display plasticity by dynamically shifting between phenotypes in response to specific signals. Each of these distinct cell profiles is associated with diverse biomarkers which may be exploited for therapeutic intervention, including IL-10, IL-13, PPAR-γ, LXR, NLRP3 inflammasomes, and microRNAs. Direct modulation of the molecular pathways concerning these potential macrophage-related targets represents a promising field for new therapeutic alternatives in atherosclerosis and CVD.

M2b macrophage polarization and its roles in diseases

“…Accumulating evidences have shown that TNF‐α, in combination with other markers, such as IL‐10, LIGHT, CCL1, or/and IL‐6, can discriminate M2b from the other subtypes of macrophages very well . In addition, TNF‐α is considered a marker of M2b macrophages in many review articles …”

PPAR-gamma Signaling in Metabolic Homeostasis

“…It has been shown that they play an important role in the modulation of inflammatory, fibrotic and hypertrophic responses. (17,20,21,23) Action of PPAR-γ agonists is not only of metabolism in insulin-responsive tissues, yet more directly in the inflammatory, cardiac and vascular cells associated with CVD such as coronary heart disease, atherosclerosis, and stroke. (17,22) PPAR-γ expressed in macrophages, endothelial cells, and smooth muscle cells in normal vasculature, and atherosclerotic lesions.…”

“…(22) In addition to effects of PPAR-γ in the arterial wall that might influence the occurrence atherothrombotic events, experimental evidence suggest that PPAR-γ activation may mitigate ischemia reperfusion injury (IRI) if such events occur. (20,21,23,24) Different cell types are reported to have different mechanisms for PPAR-γ to inhibit inflammation. (21) PPAR-γ agonists have been shown to block the proliferation and increase the apoptosis of vascular smooth muscle cells, suggesting more beneficial of PPAR-γ activation in vasculature.…”

“…(25) The importance of macrophage PPAR-γ in CVD has begun to be appreciated ever since foam cells in atherosclerotic lesions were found to have a high level of PPAR-γ expression. (19)(20)(21)23).…”

Tribbles homolog 1 enhances cholesterol efflux from oxidized low-density lipoprotein-loaded THP-1 macrophages

“…Macrophages are involved in various aspects of atherosclerosis (3,4). In particular, macrophage-mediated uptake of modified low-density lipoprotein (LDL) and subsequent transformation into foam cells serve a critical role in the development of atherosclerosis (5).…”