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Macrophages heterogeneity in atherosclerosis - implications for therapy.

Wilson HM - J. Cell. Mol. Med. (2010)

Bottom Line: As well as modulating lipid metabolism, macrophages secrete inflammatory cytokines, chemokines and reactive oxygen and nitrogen species that drive pathogenesis.Pharmacological modulation of macrophage activity therefore represents a potential therapeutic strategy 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.

View Article: PubMed Central - PubMed

Affiliation: School of Medicine and Dentistry, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, UK. h.m.wilson@abdn.ac.uk

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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.
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fig01: 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.

Mentions: Macrophage heterogeneity exists in tissue in vivo although the phenotype observed may not directly correspond to simplistic phenotypes generated in vitro. In vivo, macrophages are exposed to a complex microenvironment generated from several cell types. The way infiltrating macrophages are activated is dictated by a multitude of signals impinging on their receptors (see Fig. 1). These signals change during the evolution of the underlying disease process and have the capacity to influence the outcome of the disease. Other less-defined macrophage subtypes induced by metabolic factors are liable to be present in atherosclerotic plaques. For example, uptake of oxidized or acetylated LDL, as a model of foam cell formation increases the expression of commonly used M1 markers and transcription factors such as iNOS, metalloproteinase-1 and NF-κB [64]. Fatty acids present in developing plaques activate an inflammatory programme; saturated fatty acids are robustly pro-inflammatory, polyunstaturated fatty acids are weakly inflammatory or neutral while omega-3 unsaturated fatty acids induce more anti-inflammatory functions [65]. Moreover, under appropriate conditions, infiltrating monocytes differentiate into osteoclast-like cells within plaques and promote lesion calcification [9], whereas macrophages exposed to particulate calcium mineral have been reported to undergo osteoclastic differentiation [66].


Macrophages heterogeneity in atherosclerosis - implications for therapy.

Wilson HM - J. Cell. Mol. Med. (2010)

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.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3822996&req=5

fig01: 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.
Mentions: Macrophage heterogeneity exists in tissue in vivo although the phenotype observed may not directly correspond to simplistic phenotypes generated in vitro. In vivo, macrophages are exposed to a complex microenvironment generated from several cell types. The way infiltrating macrophages are activated is dictated by a multitude of signals impinging on their receptors (see Fig. 1). These signals change during the evolution of the underlying disease process and have the capacity to influence the outcome of the disease. Other less-defined macrophage subtypes induced by metabolic factors are liable to be present in atherosclerotic plaques. For example, uptake of oxidized or acetylated LDL, as a model of foam cell formation increases the expression of commonly used M1 markers and transcription factors such as iNOS, metalloproteinase-1 and NF-κB [64]. Fatty acids present in developing plaques activate an inflammatory programme; saturated fatty acids are robustly pro-inflammatory, polyunstaturated fatty acids are weakly inflammatory or neutral while omega-3 unsaturated fatty acids induce more anti-inflammatory functions [65]. Moreover, under appropriate conditions, infiltrating monocytes differentiate into osteoclast-like cells within plaques and promote lesion calcification [9], whereas macrophages exposed to particulate calcium mineral have been reported to undergo osteoclastic differentiation [66].

Bottom Line: As well as modulating lipid metabolism, macrophages secrete inflammatory cytokines, chemokines and reactive oxygen and nitrogen species that drive pathogenesis.Pharmacological modulation of macrophage activity therefore represents a potential therapeutic strategy 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.

View Article: PubMed Central - PubMed

Affiliation: School of Medicine and Dentistry, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, UK. h.m.wilson@abdn.ac.uk

Show MeSH
Related in: MedlinePlus