Monocytes and macrophages provide defence against pathogens and danger signals. These cells respond to stimulation in a fast and stimulus-specific manner by utilizing complex cascaded activation by ...lineage-determining and signal-dependent transcription factors. The complexity of the functional response is determined by interactions between triggered transcription factors and depends on the microenvironment and interdependent signalling cascades. Dysregulation of macrophage phenotypes is a major driver of various diseases such as atherosclerosis, rheumatoid arthritis and type 2 diabetes mellitus. Furthermore, exposure of monocytes, which are macrophage precursor cells, to certain stimuli can lead to a hypo-inflammatory tolerized phenotype or a hyper-inflammatory trained phenotype in a macrophage. In atherosclerosis, macrophages and monocytes are exposed to inflammatory cytokines, oxidized lipids, cholesterol crystals and other factors. All these stimuli induce not only a specific transcriptional response but also interact extensively, leading to transcriptional and epigenetic heterogeneity of macrophages in atherosclerotic plaques. Targeting the epigenetic landscape of plaque macrophages can be a powerful therapeutic tool to modulate pro-atherogenic phenotypes and reduce the rate of plaque formation. In this Review, we discuss the emerging role of transcription factors and epigenetic remodelling in macrophages in the context of atherosclerosis and inflammation, and provide a comprehensive overview of epigenetic enzymes and transcription factors that are involved in macrophage activation.
Abstract Objective Macrophages are decisive in the chronic inflammatory processes that drive atherogenesis. The purpose of this study was to explore the presence and spatial distribution of polarized ...macrophage populations in human atherosclerosis. Methods & results We used transcriptomics and immunohistochemistry to analyze macrophage subset dynamics in successive stages of atherogenesis. Developing lesions progressively accumulated both M1 and M2 cells, as was signified by the enhanced expression of associated markers at the transcriptional and protein level. Histologically, these markers were confined to overlapping, but spatially distinct CD68+ areas of the intima. We subsequently quantified the presence of these markers in relation to morphological determinants of plaque stability. In line with their pro-inflammatory characteristics, M1 macrophages dominated the rupture-prone shoulder regions of the plaque over M2 polarized cells, while the fibrous caps of lesions showed no significant differences between subsets. In contrast, vascular adventitial tissue displayed a pronounced M2 activation profile. As expected, areas of intraplaque hemorrhage clearly associated with CD163 staining. Rather than being limited to complicated lesions, this M2 marker was also readily detectable in stable plaques. Finally, foamy macrophages displayed an ambiguous repertoire that incorporates individual M1 and M2 markers. Conclusion M1 and M2 macrophage populations are present throughout atherogenesis. These subsets display disparity when it comes to their prevalence in morphological compartments of the vessel wall. Our current findings warrant continued investigation into the functional implications of polarized macrophage populations in human atherosclerosis.
Objective
Macrophages show extreme heterogeneity and different subsets have been characterized by their activation route and their function. For instance, macrophage subsets are distinct by acting ...differently under pathophysiological conditions such as inflammation and cancer. Macrophages also contribute to angiogenesis, but the role of various specific subsets in angiogenesis has not been thoroughly investigated.
Methods and results
Matrigel supplemented with macrophage subsets induced by IFNγ (M1), IL-4 (M2a) or IL-10 (M2c) was injected subcutaneously in C57BL/6 J mice and analyzed by CD31 staining after 14 days. Increased numbers of endothelial cells and tubular structures were observed in M2-enriched plugs compared to control and other subsets. Additionally, more tubular structures formed in vitro in the presence of M2 macrophages or their conditioned medium. To identify a mechanism for the pro-angiogenic effect, gene expression of angiogenic growth factors was analyzed. Induced expression of basic fibroblast growth factor (
Fgf2
), insulin-like growth factor-1 (
Igf1
), chemokine (C–C motif) ligand 2 (
Ccl2
) and placental growth factor (
Pgf
) was observed in M2 macrophages. Using a blocking antibody of PlGF to inhibit M2c induced angiogenesis resulted in mildly reduced (40 %) tube formation whereas neutralization of FGF-2 (M2a) signaling by sFGFR1-IIIc affected tube formation by nearly 75 %.
Conclusions
These results indicate that macrophages polarized towards an M2 phenotype have a higher angiogenic potential compared to other subsets. Furthermore, we propose FGF signaling for M2a- and PlGF signaling for M2c-induced angiogenesis as possible working mechanisms, yet, further research should elucidate the exact mechanism for M2-induced angiogenesis.
Aging is a complex process with an impact on essentially all organs. Declined cellular repair causes increased damage at genomic and proteomic levels upon aging. This can lead to systemic changes in ...metabolism and pro-inflammatory cytokine production, resulting in low-grade inflammation, or ‘inflammaging’. Tissue macrophages, gatekeepers of parenchymal homeostasis and integrity, are prime inflammatory cytokine producers, as well as initiators and regulators of inflammation. In this opinion piece, we summarize intrinsic alterations in macrophage phenotype and function with age. We propose that alternatively activated macrophages (M2-like), which are yet pro-inflammatory, can accumulate in tissues and promote inflammaging. Age-related increases in endoplasmic reticulum stress and mitochondrial dysfunction might be cell-intrinsic forces driving this unusual phenotype.
Aging is associated at the cellular level with several adaptations, fueled by increasing damage and reduced capacity for repair. This generates a condition of low-grade inflammation, called ‘inflammaging’.
Macrophages are prime cells in initiation and regulation of inflammatory processes and may thus play major roles in inflammaging.
Macrophage polarization and activation, induced by intrinsic or extrinsic conditions, are reflected in and regulated by the cells’ metabolic and epigenetic profiles.
Age-induced changes in macrophages are diverse and, in general, may represent pro-inflammatory activation of cells with an alternatively activated (M2-like) phenotype.
Viral myocarditis results from an adverse immune response to cardiotropic viruses, which causes irreversible myocyte destruction and heart failure in previously healthy people. The involvement of ...microRNAs and their usefulness as therapeutic targets in this process are unknown.
To identify microRNAs involved in viral myocarditis pathogenesis and susceptibility.
Cardiac microRNAs were profiled in both human myocarditis and in Coxsackievirus B3-injected mice, comparing myocarditis-susceptible with nonsusceptible mouse strains longitudinally. MicroRNA responses diverged depending on the susceptibility to myocarditis after viral infection in mice. MicroRNA-155, -146b, and -21 were consistently and strongly upregulated during acute myocarditis in both humans and susceptible mice. We found that microRNA-155 expression during myocarditis was localized primarily in infiltrating macrophages and T lymphocytes. Inhibition of microRNA-155 by a systemically delivered LNA-anti-miR attenuated cardiac infiltration by monocyte-macrophages, decreased T lymphocyte activation, and reduced myocardial damage during acute myocarditis in mice. These changes were accompanied by the derepression of the direct microRNA-155 target PU.1 in cardiac inflammatory cells. Beyond the acute phase, microRNA-155 inhibition reduced mortality and improved cardiac function during 7 weeks of follow-up.
Our data show that cardiac microRNA dysregulation is a characteristic of both human and mouse viral myocarditis. The inflammatory microRNA-155 is upregulated during acute myocarditis, contributes to the adverse inflammatory response to viral infection of the heart, and is a potential therapeutic target for viral myocarditis.
Macrophages are innate immune cells that adopt diverse activation states in response to their microenvironment. Editing macrophage activation to dampen inflammatory diseases by promoting the ...repolarization of inflammatory (M1) macrophages to anti-inflammatory (M2) macrophages is of high interest. Here, we find that mouse and human M1 macrophages fail to convert into M2 cells upon IL-4 exposure in vitro and in vivo. In sharp contrast, M2 macrophages are more plastic and readily repolarized into an inflammatory M1 state. We identify M1-associated inhibition of mitochondrial oxidative phosphorylation as the factor responsible for preventing M1→M2 repolarization. Inhibiting nitric oxide production, a key effector molecule in M1 cells, dampens the decline in mitochondrial function to improve metabolic and phenotypic reprogramming to M2 macrophages. Thus, inflammatory macrophage activation blunts oxidative phosphorylation, thereby preventing repolarization. Therapeutically restoring mitochondrial function might be useful to improve the reprogramming of inflammatory macrophages into anti-inflammatory cells to control disease.
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•Mouse and human M1 macrophages fail to repolarize to M2 upon IL-4 restimulation•LPS + IFNγ treatment inhibits mitochondrial oxidative respiration in macrophages•Mitochondrial function is required for the repolarization to an M2 phenotype•NO blunts mitochondrial respiration and prevents plasticity in M1 macrophages
Editing macrophage polarization is an emerging concept for the treatment of inflammatory diseases. Van den Bossche et al. show that inflammatory M1 macrophage activation dampens mitochondrial function, thereby preventing the repolarization to an anti-inflammatory M2 phenotype. Inhibiting nitric oxide production improves mitochondrial function and reprogramming to M2 macrophages.
Several studies have suggested a role for the gut microbiota in inflammation and atherogenesis. A causal relation relationship between gut microbiota, inflammation, and atherosclerosis has not been ...explored previously.
Here, we investigated whether a proinflammatory microbiota from Caspase1
( Casp1
) mice accelerates atherogenesis in Ldlr
mice.
We treated female Ldlr
mice with antibiotics and subsequently transplanted them with fecal microbiota from Casp1
mice based on a cohousing approach. Autologous transplantation of fecal microbiota of Ldlr
mice served as control. Mice were cohoused for 8 or 13 weeks and fed chow or high-fat cholesterol-rich diet. Fecal samples were collected, and factors related to inflammation, metabolism, intestinal health, and atherosclerotic phenotypes were measured. Unweighted Unifrac distances of 16S rDNA (ribosomal DNA) sequences confirmed the introduction of the Casp1
and Ldlr
microbiota into Ldlr
mice (referred to as Ldlr
( Casp1
) or Ldlr
( Ldlr
) mice). Analysis of atherosclerotic lesion size in the aortic root demonstrated a significant 29% increase in plaque size in 13-week high-fat cholesterol-fed Ldlr
( Casp1
) mice compared with Ldlr
( Ldlr
) mice. We found increased numbers of circulating monocytes and neutrophils and elevated proinflammatory cytokine levels in plasma in high-fat cholesterol-fed Ldlr
( Casp1
) compared with Ldlr
( Ldlr
) mice. Neutrophil accumulation in the aortic root of Ldlr
( Casp1
) mice was enhanced compared with Ldlr
( Ldlr
) mice. 16S-rDNA-encoding sequence analysis in feces identified a significant reduction in the short-chain fatty acid-producing taxonomies Akkermansia, Christensenellaceae, Clostridium, and Odoribacter in Ldlr
( Casp1
) mice. Consistent with these findings, cumulative concentrations of the anti-inflammatory short-chain fatty acids propionate, acetate and butyrate in the cecum were significantly reduced in 13-week high-fat cholesterol-fed Ldlr
( Casp1
) compared with Ldlr
( Ldlr
) mice.
Introduction of the proinflammatory Casp1
microbiota into Ldlr
mice enhances systemic inflammation and accelerates atherogenesis.
microRNA-155 (miR155) is a central regulator of immune responses that is induced by inflammatory mediators. Although miR155 is considered to be a pro-inflammatory microRNA, in vitro reports show ...anti-inflammatory effects in lipid-loaded cells. In this study we examined the role of miR155 in atherosclerosis in vivo using bone marrow transplantation from miR155 deficient or wildtype mice to hyperlipidemic mice. Hematopoietic deficiency of miR155 enhanced atherosclerotic plaque development and decreased plaque stability, as evidenced by increased myeloid inflammatory cell recruitment to the plaque. The increased inflammatory state was mirrored by a decrease in circulating CD4(+)CD25(+)FoxP3(+) regulatory T cells, and an increase in granulocytes (CD11b(+)Ly6G(+)) in blood of miR155(-/-) transplanted mice. Moreover, we show for the first time a crucial role of miR155 in monocyte subset differentiation, since hematopoietic deficiency of miR155 increases the 'inflammatory' monocyte subset (CD11b(+)Ly6G(-)Ly6C(hi)) and reduces 'resident' monocytes (CD11b(+)Ly6G(-)Ly6C(low)) in the circulation. Furthermore, cytokine production by resident peritoneal macrophages of miR155(-/-) transplanted hyperlipidemic mice was skewed towards a more pro-inflammatory state since anti-inflammatory IL-10 production was reduced. In conclusion, in this hyperlipidemic mouse model miR155 acts as an anti-inflammatory, atheroprotective microRNA. Additionally, besides a known role in lymphoid cell development, we show a crucial role of miR155 in myeloid lineage differentiation.
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