Epigenetic regulation of the alternatively activated macrophage phenotype

Immunology Program, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
Blood (Impact Factor: 10.45). 07/2009; 114(15):3244-54. 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.

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    • "Overall, our serial BM transplant studies support the concept that obesity can durably reprogram the output of BM progenitors and that this is taking place at the level of long term repopulating (LT) HSCs. We hypothesize that obesity-induced epigenetic changes may play a role in generating this phenotype as this has been shown to influence macrophage activation states after chronic and acute inflammatory stimuli [56,57]. The preferential accumulation of CD11c+ ATMs and crown-like structures was not associated with any significant derangements in glucose metabolism in lean or obese conditions in the serial transplant. "
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    ABSTRACT: Obesity is associated with an activated macrophage phenotype in multiple tissues that contributes to tissue inflammation and metabolic disease. To evaluate the mechanisms by which obesity potentiates myeloid activation, we evaluated the hypothesis that obesity activates myeloid cell production from bone marrow progenitors to potentiate inflammatory responses in metabolic tissues. High fat diet-induced obesity generated both quantitative increases in myeloid progenitors as well as a potentiation of inflammation in macrophages derived from these progenitors. In vivo, hematopoietic stem cells from obese mice demonstrated the sustained capacity to preferentially generate inflammatory CD11c+ adipose tissue macrophages after serial bone marrow transplantation. We identified that hematopoietic MyD88 was important for the accumulation of CD11c+ adipose tissue macrophage accumulation by regulating the generation of myeloid progenitors from HSCs. These findings demonstrate that obesity and metabolic signals potentiate leukocyte production and that dietary priming of hematopoietic progenitors contributes to adipose tissue inflammation.
    Molecular Metabolism 09/2014; 3(6). DOI:10.1016/j.molmet.2014.06.005
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    • "In the macrophage lineage, in addition to its role during differentiation , Kdm6b expression shows rapid (time course of hours) induction in response to macrophage-activating stimuli, including bacterial lipopolysaccharides (LPS), cytokines, and TNFα (De Santa et al., 2007, 2009; Ishii et al., 2009; Kruidenier et al., 2012). In these cells Kdm6b contributes to the regulation of several hundred LPS-induced genes (De Santa et al., 2009). "
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    ABSTRACT: Enzymes that regulate histone lysine methylation play important roles in neuronal differentiation, but little is known about their contributions to activity-regulated gene transcription in differentiated neurons. We characterized activity-regulated expression of lysine demethylases and lysine methyltransferases in the hippocampus of adult male mice following pilocarpine-induced seizure. Pilocarpine drove a 20-fold increase in mRNA encoding the histone H3 lysine27-specific demethylase Kdm6b selectively in granule neurons of the dentate gyrus, and this induction was recapitulated in cultured hippocampal neurons by bicuculline and 4-aminopyridine (Bic+4AP) stimulation of synaptic activity. Because activity-regulated gene expression is highly correlated with neuronal survival, we tested the requirement for Kdm6b expression in Bic+4AP induced preconditioning of neuronal survival. Prior exposure to Bic+4AP promoted neuronal survival in control neurons upon growth factor withdrawal, however this effect was ablated when we knocked down Kdm6b expression. Loss of Kdm6b did not disrupt activity-induced expression of most genes, including that of a gene set previously established to promote neuronal survival in this assay. However using bioinformatic analysis of RNA sequencing data, we discovered that Kdm6b knockdown neurons showed impaired inducibility of a discrete set of genes annotated for their function in inflammation. These data reveal a novel function for Kdm6b in activity-regulated neuronal survival, and they suggest that activity- and Kdm6b-dependent regulation of inflammatory gene pathways may serve as an adaptive pro-survival response to increased neuronal activity.
    Molecular and Cellular Neuroscience 06/2014; 61. DOI:10.1016/j.mcn.2014.06.008 · 3.84 Impact Factor
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    • "In addition, p50- deficient mice exhibit exacerbated M1-driven inflammatory responses with a concomitant suppression of M2-driven responses (allergy and anti-helminth immunity). In addition to p50 NFκB, M2-like differentiation/ polarisation has been demonstrated to be induced by agonists of PPARγ [32], CREB-controlled C/EBPβ [33] and epigenetic regulation of M2- defining gene products in mice (arginase-1, Ym1, FIZZ1 and mannose receptor) via the IL-4- STAT6-dependent histone demethylation of H3 by the histone demethylase, jmjd3 [34] [35]. "
    Immune response activation, Edited by Guy Huynh Thien Duc, 05/2014: chapter Macrophages: masters of immune activation, suppression and deviation: pages 121-149; InTech., ISBN: 980-953-307-1094-2
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