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Epigenetic regulation of the alternatively activated macrophage phenotype.

ABSTRACT: Alternatively activated (M2) macrophages play critical roles in diverse chronic diseases, including parasite infections, cancer, and allergic responses. However, little is known about the acquisition and maintenance of their phenotype. We report that M2-macrophage marker genes are epigenetically regulated by reciprocal changes in histone H3 lysine-4 (H3K4) and histone H3 lysine-27 (H3K27) methylation; and the latter methylation marks are removed by the H3K27 demethylase Jumonji domain containing 3 (Jmjd3). We found that continuous interleukin-4 (IL-4) treatment leads to decreased H3K27 methylation, at the promoter of M2 marker genes, and a concomitant increase in Jmjd3 expression. Furthermore, we demonstrate that IL-4-dependent Jmjd3 expression is mediated by STAT6, a major transcription factor of IL-4-mediated signaling. After IL-4 stimulation, activated STAT6 is increased and binds to consensus sites at the Jmjd3 promoter. Increased Jmjd3 contributes to the decrease of H3K27 dimethylation and trimethylation (H3K27me2/3) marks as well as the transcriptional activation of specific M2 marker genes. The decrease in H3K27me2/3 and increase in Jmjd3 recruitment were confirmed by in vivo studies using a Schistosoma mansoni egg-challenged mouse model, a well-studied system known to support an M2 phenotype. Collectively, these data indicate that chromatin remodeling is mechanistically important in the acquisition of the M2-macrophage phenotype.

SUBMITTER: Ishii M

PROVIDER: S-EPMC2759649 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Epigenetic regulation of the alternatively activated macrophage phenotype.

Ishii Makoto M Wen Haitao H Corsa Callie A S CA Liu Tianju T Coelho Ana L AL Allen Ronald M RM Carson William F WF Cavassani Karen A KA Li Xiangzhi X Lukacs Nicholas W NW Hogaboam Cory M CM Dou Yali Y Kunkel Steven L SL

Blood 20090630 15

Alternatively activated (M2) macrophages play critical roles in diverse chronic diseases, including parasite infections, cancer, and allergic responses. However, little is known about the acquisition and maintenance of their phenotype. We report that M2-macrophage marker genes are epigenetically regulated by reciprocal changes in histone H3 lysine-4 (H3K4) and histone H3 lysine-27 (H3K27) methylation; and the latter methylation marks are removed by the H3K27 demethylase Jumonji domain containing ...[more]

PMID: 19567879

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Project description:BackgroundAlternatively activated (M2) macrophages are phenotypically characterized by the expression of specific markers, mainly macrophage scavenger receptors (CD204 and CD163) and mannose receptor-1 (CD206), and participate in the fibrotic process by over-producing pro-fibrotic molecules, such as transforming growth factor-beta1 (TGFbeta1) and metalloproteinase (MMP)-9. Endothelin-1 (ET-1) is implicated in the fibrotic process, exerting its pro-fibrotic effects through the interaction with its receptors (ETA and ETB). The study investigated the possible role of ET-1 in inducing the transition from cultured human macrophages into M2 cells.MethodsCultured human monocytes (THP-1 cell line) were activated into macrophages (M0 macrophages) with phorbol myristate acetate and subsequently maintained in growth medium (M0-controls) or treated with either ET-1 (100nM) or interleukin-4 (IL-4, 10ng/mL, M2 inducer) for 72 hours. Similarly, primary cultures of human peripheral blood monocyte (PBM)-derived macrophages obtained from healthy subjects, were maintained in growth medium (untreated cells) or treated with ET-1 or IL-4 for 6 days. Both M0 and PBM-derived macrophages were pre-treated with ET receptor antagonist (ETA/BRA, bosentan 10-5M) for 1 hour before ET-1 stimulation. Protein and gene expression of CD204, CD206, CD163, TGFbeta1 were analysed by immunocytochemistry, Western blotting and quantitative real time polymerase chain reaction (qRT-PCR). Gene expression of interleukin(IL)-10 and macrophage derived chemokine (CCL-22) was evaluated by qRT-PCR. MMP-9 production was investigated by gel zymography.ResultsET-1 significantly increased the expression of M2 phenotype markers CD204, CD206, CD163, IL-10 and CCL-22, and the production of MMP-9 in both cultures of M0 and PBM-derived macrophages compared to M0-controls and untreated cells. In cultured PBM-derived macrophages, ET-1 increased TGFbeta1 protein and gene expression compared to untreated cells. The ET-1-mediated effects were contrasted by ETA/BRA treatment in both cultured cell types.ConclusionET-1 seems to induce the M2 phenotype in cultured human macrophages, a process apparently contrasted by the action of the ETA/BRA, suggesting possible clinical implications in those fibrotic diseases characterized by increased ET-1 concentrations, such as systemic sclerosis but also type 2 diabetes.

Project description:Alternatively activated macrophages have been reported to be helpful to alleviate systematic lupus erythematosus (SLE), and azithromycin could serve as an immunomodulator by promoting alternatively activated macrophage phenotype. However, the effect of azithromycin in SLE and the involved mechanism remain undetermined. The aim of this study is to characterize azithromycin and the underlying mechanism contributing to SLE therapy. First, we compared monocytes from SLE patients and matched healthy donors, and found monocytes from SLE patients exhibited more CD14+CD86+ cells, impaired phagocytic activity, and elevated interleukin (IL)-1?, IL-6, and tumor necrosis factor (TNF)-? (the classical activated phenotype), which could be blocked by azithromycin. On the contrary, there were fewer CD14+CD163+ cells in SLE patients, accompanied by decreased arginase (Arg)-1 and found in inflammatory zone (Fizz)-1 (the alternatively activated phenotype). And IL-10, the crucial immune regulatory factor secreted by alternatively activated monocytes/macrophages, also showed a decreased trend in SLE patients. In addition, all these markers were up-regulated after azithromycin treatment. Next, we used activated lymphocyte-derived-DNA to imitate SLE macrophages in vitro to investigate the possible mechanism involved. Azithromycin showed the same effect in imitated SLE macrophages, with distinct Akt phosphorylation at 30?min and 12?h. After inhibiting Akt phosphorylation by LY294002, the down-regulation of CD80, IL-1?, IL-6, and TNF-? caused by azithromycin raised again, meanwhile, the up-regulation of CD206, Arg-1, Fizz-1, and IL-10 due to azithromycin was abolished. Additionally, insulin-like growth factor 1 (IGF-1), the specific agonist of Akt, played a similar role to azithromycin in imitated SLE macrophages. Taken together, our data indicated a novel role of azithromycin in alleviating SLE by promoting alternatively activated macrophage phenotype, and the PI3K/Akt signaling pathway was involved. Our findings provide a rationale for further investigation of novel therapeutic strategy for SLE patients.

Project description:BackgroundMeans to promote endogenous remyelination in multiple sclerosis (MS) benefit from insights into the role of inhibitory molecules that preclude remyelination. Fibronectin assembles into aggregates in MS, which impair oligodendrocyte differentiation and remyelination. Microglia and macrophages are required for complete remyelination and normally switch from a pro-inflammatory classical phenotype upon demyelination to a supportive alternative phenotype during remyelination. Here, we investigated the role of fibronectin aggregates in modulating microglia and macrophage behavior and phenotypes.MethodsBone marrow-derived macrophages and microglia from newborn rats were exposed to (a) plasma fibronectin coatings; (b) coatings of deoxycholate-insoluble fibronectin aggregates; (c) interferon-γ (IFNγ) treatment, as an inducer of the pro-inflammatory classically activated phenotype; (d) interleukin-4 (IL-4) treatment, to promote the pro-regenerative anti-inflammatory alternatively activated phenotype; or (e) left unstimulated on uncoated plastic. To examine the in vitro effects of the different stimulations on cell behavior and phenotype, proliferation, phagocytosis, morphology, and pro- and anti-inflammatory features were assessed.ResultsIn line with a classically activated phenotype, exposure of microglia and macrophages to both plasma fibronectin and fibronectin aggregates induced an amoeboid morphology and stimulated phagocytosis by macrophages. Furthermore, as observed upon IFNγ treatment, coatings of aggregated, but not plasma fibronectin, promoted nitric oxide release by microglia and macrophages. Remarkably, fibronectin aggregates induced nitric oxide release in an integrin-independent manner. In addition, fibronectin aggregates, but not plasma fibronectin, increased the expression of arginase-1, similarly as observed upon treatment with IL-4. Proteomic analysis revealed that aggregates of fibronectin act as a scaffold for other proteins, including Hsp70 and thrombospondin-1, which may clarify the induction of both pro-inflammatory and anti-inflammatory features in macrophages cultured on fibronectin aggregate, but not plasma fibronectin coatings.ConclusionsMacrophages and microglia grown on aggregated fibronectin coatings adopt a distinct phenotype compared to plasma fibronectin coatings, showing pro-inflammatory and anti-inflammatory features. Therefore, the pathological fibronectin aggregates in MS lesions may impair remyelination by promoting and/or retaining several classically activated phenotypic features in microglia and macrophages.

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Epigenetic regulation of the alternatively activated macrophage phenotype.

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Epigenetic regulation of the alternatively activated macrophage phenotype.

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