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 wellstudied 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. (Blood. 2009;114:3244-3254)

Jmjd3 is essential for the epigenetic modulation of microglia phenotypes in the immune pathogenesis of Parkinson’s disease

“…33 Several other studies have also shown that M1 classical responses and NO production do not differ between wild-type and Jmjd3-deficient macrophages. 33,34 However, our findings have revealed that Figure 5 Arginase1 prevents neuron death through counteracting iNOS. (a) N9 cells were infected with pLKO-kdNC, pLKO-kdJmjd3, pLKO-kdArginase1 lentiviruses, as well as pLKO-kdJmjd3/pLVX-Arginase1 mixed lentiviruses.…”

Epigenetic modifiers reduce inflammation and modulate macrophage phenotype during endotoxemia-induced acute lung injury

“…Lung alveolar macrophages (Lin et al, 2008) play a pivotal role in the pathogenesis of ALI, and plasticity of M1 and M2 macrophages takes place because of bacterial products, which -in turn -result in the inflammation of lung tissue. M2 macrophages are involved in tissue repair and remodeling (Ishii et al, 2009;Wynn, 2004). The genes expressed by the macrophages can be phenotypically characterized as M1 (inflammatory) and M2 (anti-inflammatory) macrophages.…”

Small cell lung cancer: Recruitment of macrophages by circulating tumor cells

“…29,30 CHI3L3 was described as typical marker of M2 macrophages in mice. 31 According to our results, CHI3L1 pseudochitinase is the corresponding counterpart in humans where it constitutes an important regulator of inflammation, angiogenesis and M2 macrophage differentiation in addition to its expression by SCLC CTCs. 12,32 Specifically, M2b macrophages are activated by immune complexes, toll-like receptor-positive lymphocytes, or IL-1ra.…”