Diversity of macrophage phenotypes and responses in atherosclerosis - PubMed (original) (raw)
Review
. 2020 May;77(10):1919-1932.
doi: 10.1007/s00018-019-03371-3. Epub 2019 Nov 12.
Liang Guo 1, Atsushi Sakamoto 1, Sho Torii 1, Yu Sato 1, Anne Cornelissen 1, Salome Kuntz 1, Ka Hyun Paek 1, Raquel Fernandez 1, Daniela Fuller 1, Neel Gadhoke 1, Dipti Surve 1, Maria Romero 1, Frank D Kolodgie 1, Renu Virmani 1, Aloke V Finn 2
Affiliations
- PMID: 31720740
- PMCID: PMC11104939
- DOI: 10.1007/s00018-019-03371-3
Review
Diversity of macrophage phenotypes and responses in atherosclerosis
Hiroyuki Jinnouchi et al. Cell Mol Life Sci. 2020 May.
Abstract
The presence of macrophages within the plaque is a defining hallmark of atherosclerosis. Macrophages are exposed to various microenvironments such as oxidized lipids and cytokines which effect their phenotypic differentiation and activation. Classically, macrophages have been divided into two groups: M1 and M2 macrophages induced by T-helper 1 and T-helper 2 cytokines, respectively. However, for a decade, greater phenotypic heterogeneity and plasticity of these cells have since been reported in various models. In addition to M1 and M2 macrophage phenotypes, the concept of additional macrophage phenotypes such as M (Hb), Mox, and M4 has emerged. Understanding the mechanisms and functions of distinct phenotype of macrophages can lead to determination of their potential role in atherosclerotic plaque pathogenesis. However, there are still many unresolved controversies regarding their phenotype and function with respect to atherosclerosis. Here, we summarize and focus on the differential subtypes of macrophages in atherosclerotic plaques and their differing functional roles based upon microenvironments such as lipid, intraplaque hemorrhage, and plaque regression.
Keywords: Hemorrhage; Lipid; Macrophage; Phenotype.
Conflict of interest statement
The authors declare that they have no conflict of interest.
Figures
Fig. 1
Main macrophage subtypes found in atherosclerotic lesions. Stimuli present in atherosclerotic lesions drive the differentiation of monocytes towards different macrophage phenotypes. a M1 macrophages release pro-inflammatory cytokines. b M (Hb), Mhem, and M2 macrophages are resistant to lipid accumulation, possess iron-handling capacities, and have anti-inflammatory effects. c Mox macrophages display an antioxidant gene expression profile. d M4 macrophages, like M1 macrophages, are pro-inflammatory, but lack the capacity for phagocytosis. COX-2 cyclooxygenase, CXCL4 C-X-C motif chemokine 4, HMOX-1 haem oxygenase (decycling) 1, LDL low-density lipoprotein, LXR liver X receptor, MMP-7 matrix metalloproteinase-7, NFE2L2 nuclear factor (erythroid-derived 2)-like 2, NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells, TLR toll-like receptor, TNF tumor necrosis factor (Ref. [33])
Fig. 2
M2 markers CD206/CD163 are present in human atherosclerotic lesions at sites of prior hemorrhage and are distinct from foam cells. a Representative frozen section of human coronary fibroatheroma from a 48-year-old man who died suddenly. High-power image from ctrl (red box) shows foamy macrophages in the perinecrotic core (NC) region. The blue box shows an area rich in angiogenesis and iron (low-power image, Movat stain; high-power images, hematoxylin and eosin [H&E] stain). Photomicrographs of the boxed areas from ctrl (red boxes) (c–j) and area of angio/hemo/iron (blue boxes) (k–r). Note that the ctrl area shows a lack of CD31 staining (brown). b Plaque regions were identified by the presence of angiogenesis/hemorrhage/iron (angio/hemo/iron) and compared with control (ctrl) pericore regions of macrophages devoid of angio/hemo/iron (c), abundant oil red O (ORO) positivity (red) (d), macrophage infiltration (CD68, brown) (e), CD36 staining (brown) (f) and no iron staining (blue, Perls’ Prussian blue) (g). It also demonstrates abundant tumor necrosis factor (TNF-) positivity (brown) (h), but there is minimal MR (CD206, brown) (i) and CD163 (brown) (j) immunostaining. k–r From an area of angio/hemo/iron showing abundant CD31 staining (k, black arrows point to angiogenesis), rare positive cells for oil red O (l), but abundant C68 staining (m). This area also demonstrates minimal CD36 staining (n), but abundance of iron (o), minimal TNF staining (p), but positive staining for CD206 and CD163 (q, r). Quantitative analysis (s) from ctrl and angio/hemo/iron areas from 14 plaques demonstrated equivalent macrophage area density (CD68) but higher expression of CD163 and CD206 in regions of angio/hemo/iron than in ctrl regions. Scale bars: low-power, 2 mm; high-power: 200 m (non-normal distribution CD68 and CD163). Fe iron (Ref. [71])
Fig. 3
Summary of the role of M (Hb) macrophages in plaque angiogenesis, permeability, vascular inflammation, and plaque progression. In areas of IPH, HH complex ingestion by macrophages induces angiogenesis via activation of HIF1α, which is a consequence of intracellular Fe2+ deprivation and PHD2 inhibition. VEGF-A, which is secreted by macrophages via HIF1α activation, promotes angiogenesis, endothelial expression of VCAM, inflammatory cell recruitment, and vascular permeability via VEGF-A/VEGFR2 signaling. This may cause further IPH, RBC lysis, and more Hb ingestion by CD163+ macrophages. This vicious cycle causes plaque progression, which eventually leads to plaque rupture (Ref. [82])
References
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