Epigenetic regulation of the alternatively activated macrophage phenotype

ArticleinBlood 114(15):3244-54 · July 2009with15 Reads
Impact Factor: 10.45 · DOI: 10.1182/blood-2009-04-217620 · Source: PubMed

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.

    • "More specifically, methylation of histone H3 33 at lysine-9 and -27, and histone H4 at lysine-20 were found to be related with repression of transcription. (Ishii, et al., 2009). In their studies it was demonstrated that M2-macrophages are epigenetically regulated. "
    [Show description] [Hide description] DESCRIPTION: Part I: Identifying target genes for the demethylase JmJD2c Part II: Investigating the plasticity of pro-inflammatory (M1) and anti-inflammatory (M2) macrophages
    Full-text · Research · Apr 2016
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    • "This result suggests that JMJD3 may also be induced by alternative activation. Indeed, JMJD3 is expressed in IL-4-stimulated BMDM as a direct downstream target of STAT6 [50] and promotes the expression of Irf4 to establish a M2 phenotype [51]. Recently, a novel family of Fe 2+ -and 2-oxoglutarate- dependent dioxygenases [110] , named ten-eleven translocation (TET) proteins (reviewed in [111]), were found to take part in a number of biological processes, such as embryonic development [112] and epigenetic regulation of gene transcription and cancer [113] , and mediate their effects by oxidising 5-methylcytosine in DNA to 5-hydroxymethylcytosine, 5- formylcytosine, and 5-carboxylcytosine [114, 115]. "
    [Show abstract] [Hide abstract] ABSTRACT: Macrophages function as sentinel cells, which constantly monitor the host environment for infection or injury. Macrophages have been shown to exhibit a spectrum of activated phenotypes, which can often be categorised under the M1/M2 paradigm. M1 macrophages secrete proinflammatory cytokines and chemokines, such as TNF- α , IL-6, IL-12, CCL4, and CXCL10, and induce phagocytosis and oxidative dependent killing mechanisms. In contrast, M2 macrophages support wound healing and resolution of inflammation. In the past decade, interest has grown in understanding the mechanisms involved in regulating macrophage activation. In particular, epigenetic control of M1 or M2 activation states has been shown to rely on posttranslational modifications of histone proteins adjacent to inflammatory-related genes. Changes in methylation and acetylation of histones by methyltransferases, demethylases, acetyltransferases, and deacetylases can all impact how macrophage phenotypes are generated. In this review, we summarise the latest advances in the field of epigenetic regulation of macrophage polarisation to M1 or M2 states, with particular focus on the cytokine and chemokine profiles associated with these phenotypes.
    Full-text · Article · Apr 2016 · Mediators of Inflammation
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    • "Both IL-4 and IL-13 signal through the JAK-STAT pathway, leading to the activation of STAT6. Signaling through STAT6 has been shown to be essential for the expression of several M2 macrophage markers [18]. In M2 macrophages, the production of NO is diminished due to the blockage of iNOS, but cytokines, such as TGFβ, IL-10 and the IL-1 receptor antagonist, are produced. "
    [Show abstract] [Hide abstract] ABSTRACT: To diminish heart failure development after acute myocardial infarction (AMI), several preclinical studies have focused on influencing the inflammatory processes in the healing response post-AMI. The initial purpose of this healing response is to clear cell debris of the injured cardiac tissue and to eventually resolve inflammation and support scar tissue formation. This is a well-balanced reaction. However, excess inflammation can lead to infarct expansion, adverse ventricular remodeling and thereby propagate heart failure development. Different macrophage subtypes are centrally involved in both the promotion and resolution phase of inflammation. Modulation of macrophage subset polarization has been described to greatly affect the quality and outcome of healing after AMI. Therefore, it is of great interest to reveal the process of macrophage polarization to support the development of therapeutic targets. The current review summarizes (pre)clinical studies that demonstrate essential molecules involved in macrophage polarization that can be modulated and influence cardiac healing after AMI.
    Full-text · Article · Dec 2015 · International Journal of Molecular Sciences
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