Emodin Bidirectionally Modulates Macrophage Polarization and Epigenetically Regulates Macrophage Memory

Abstract

Macrophages are pleiotropic cells capable of performing a broad spectrum of functions. Macrophage phenotypes are classified along a continuum between the extremes of proinflammatory M1 macrophages and anti-inflammatory M2 macrophages. The seemingly opposing functions of M1 and M2 macrophages must be tightly regulated for an effective and proper response to foreign molecules or damaged tissue. Excessive activation of either M1 or M2 macrophages contributes to the pathology of many diseases. Emodin is a Chinese herb-derived compound and has shown potential to inhibit inflammation in various settings. In this study, we tested the ability of emodin to modulate the macrophage response to both M1 and M2 stimuli. Primary mouse macrophages were stimulated with LPS/IFN␥ or IL4 with or without emodin, and the effects of emodin on gene transcription, cell signaling pathways, and histone modifications were examined by a variety of approaches, including microarray, quantitative real-time PCR, Western blotting, chromatin immunoprecipitation, and functional assays. We found that emodin bidirectionally tunes the induction of LPS/IFN␥-and IL4-responsive genes through inhibiting NFB/IRF5/STAT1 signaling and IRF4/STAT6 signaling, respectively. Thereby, emodin modulates macrophage phagocytosis, migration, and NO production. Furthermore, emodin inhibited the removal of H3K27 trimethylation (H3K27m3) marks and the addition of H3K27 acetylation (H3K27ac) marks on genes required for M1 or M2 polarization of macrophages. In conclusion, our data suggest that emodin is uniquely able to suppress the excessive response of macrophages to both M1 and M2 stimuli and therefore has the potential to restore macrophage homeostasis in various pathologies.

Chlorogenic acid inhibits glioblastoma growth through repolarizating macrophage from M2 to M1 phenotype

“…S. Gao and S. Iwanowycz, et al . have reported that several Chinese herb-derived antioxidants, such as Curcumin and Emodin, could suppress the excessive response of M1 macrophages via blockade of NF-κB signaling pathway2044454647. But others indicated that NF-κB activation plays an important role in macrophage differentiation toward the M2 phenotype.…”

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

“…It also down-regulates CXCR4 to suppress C-X-C motif chemokine 12 (CXCL-12)-induced cell migration and invasion in hepatocellular carcinoma HepG2 and HepG3 cells [395]. In addition, emodin inhibits the differentiation of maturation of DCs [396], and can modulate macrophage polarization to restore macrophage homeostasis [397].…”

Promising landscape for regulating macrophage polarization: epigenetic viewpoint

“…Collectively, histones modifications of genes required for M1 or M2 polarization might have the therapeutic potential in various pathologies. For example, emodin seemingly to bidirectionally restore macrophage M1/M2 polarization and immune homeostasis by inhibiting the removal of H3K27 trimethylation (H3K27me3) and the addition of H3K27 acetylation (H3K27ac), respectively [ 117 ]. Ornithine decarboxylase (ODC) could inhibit gastric and colonic inflammation by the deletion of M1 macrophage responses, which accompanied by the decreased H3K4 monomethylation, H3K9 acetylation and increased H3K9 di/trimethylation in primary macrophages [ 113 ].…”