M1- and M2-Type Macrophage Responses Are Predictive of Adverse Outcomes in Human Atherosclerosis

Abstract

Atherosclerosis is an inflammatory disease caused by endothelial injury, lipid deposition, and oxidative stress. This progressive disease can be converted into an acute clinical event by plaque rupture and thrombosis. In the context of atherosclerosis, the underlying cause of myocardial infarction and stroke, macrophages uniquely possess a dual functionality, regulating lipid accumulation and metabolism and sustaining the chronic inflammatory response, two of the most well-documented pathways associated with the pathogenesis of the disease. Macrophages are heterogeneous cell populations and it is hypothesized that, during the pathogenesis of atherosclerosis, macrophages in the developing plaque can switch from a pro-inflammatory (MΦ1) to an anti-inflammatory (MΦ2) phenotype and vice versa, depending on the microenvironment. The aim of this study was to identify changes in macrophage subpopulations in the progression of human atherosclerotic disease. Established atherosclerotic plaques from symptomatic and asymptomatic patients with existing coronary artery disease undergoing carotid endarterectomy were recruited to the study. Comprehensive histological and immunohistochemical analyses were performed to quantify the cellular content and macrophage subsets of atherosclerotic lesion. In parallel, expression of MΦ1 and MΦ2 macrophage markers were analyzed by real-time PCR and Western blot analysis. Gross analysis and histological staining demonstrated that symptomatic plaques presented greater hemorrhagic activity and the internal carotid was the most diseased segment, based on the predominant prevalence of fibrotic and necrotic tissue, calcifications, and hemorrhagic events. Immunohistochemical analysis showed that both MΦ1 and MΦ2 macrophages are present in human plaques. However, MΦ2 macrophages are localized to more stable locations within the lesion. Importantly, gene and protein expression analysis of MΦ1/MΦ2 markers evidenced that MΦ1 markers and Th1-associated cytokines are highly expressed in symptomatic plaques, whereas expression of the MΦ2 markers, mannose receptor (MR), and CD163 and Th2 cytokines are inversely related with disease progression. These data increase the understanding of atherosclerosis development, identifying the cellular content of lesions during disease progression, and characterizing macrophage subpopulation within human atherosclerotic plaques.

Puerarin inhibits M2 polarization and metastasis of tumor-associated macrophages from NSCLC xenograft model via inactivating MEK/ERK 1/2 pathway

“…The expression of the M2 marker in TAMs was significantly correlated to poor prognosis and lymph node metastasis in patients with advanced adenocarcinoma (14). A report exhibited that the expression of M2 marker CD163 was significantly increased in all NSCLC subtypes (7) and in patients with progressive disease (36). Similarly, the M2 markers (CD206 + , Arg-1 + and CD163 + ) were increased in NSCLC model in the present study.…”

Beneficial Effects of Melatonin on Apolipoprotein-E Knockout Mice by Morphological and 18F-FDG PET/CT Assessments

“…M1 macrophages were abundant in vulnerable plaques whereas M2 cells were fewer in the atherosclerosis animal model. Both of these populations are plastic cells because they can switch from the M1 to M2 state and vice versa upon specific signals; the changes from M1 to M2 has been defined as "macrophage polarization" [28]. Furthermore, M1 macrophages exhibit elevated lipid accumulation, which contribute to the acceleration of atherosclerosis; whereas in contrast, M2 macrophages are located far from the lipid core of the plaque, contain smaller lipid droplets, and are involved in phagocytosis [29][30][31].…”

AMPK activation enhances the anti-atherogenic effects of high density lipoproteins in apoE−/− mice

“…Macrophages play dynamic roles in all stages of atherosclerosis development, including uptake of retained lipoproteins, secretion of pro-inflammatory and anti-inflammatory cytokines, and regulation cholesterol homeostasis ( 46 ). Macrophages are phenotypically plastic cells and two types of macrophages have been identified: M1 (a pro-inflammatory phenotype) and M2 (an anti-inflammatory phenotype) ( 47 ). Growing evidence suggests that AMPK is involved in suppressing pro-inflammatory responses by modulating macrophage polarization ( 37 ).…”