title: 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/IFNγ 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/IFNγ- and IL4-responsive genes through inhibiting NFκB/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.
authors.affiliation: From the Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina 29209 and.
authors.forename: Stephen
authors.initials: S
authors.lastname: Iwanowycz
authors.affiliation: From the Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina 29209 and.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Wang
authors.affiliation: the Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208.
authors.forename: Diego
authors.initials: D
authors.lastname: Altomare
authors.affiliation: From the Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina 29209 and.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Hui
authors.affiliation: From the Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina 29209 and daping.fan@uscmed.sc.edu.
authors.forename: Daping
authors.initials: D
authors.lastname: Fan
mesh_terms: D000818:Animals; D016764:Cell Polarity / Q000187:drug effects*; D002478:Cells, Cultured; D004642:Emodin / Q000494:pharmacology*; D057890:Epigenomics; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects*; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology*; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D000099218:Interferon Regulatory Factor-4
chemical_list: D004642:Emodin; D050835:Interferon Regulatory Factors; D015847:Interleukin-4; D016328:NF-kappa B; D000099218:Interferon Regulatory Factor-4
keywords: cell signaling; emodin; histone modification; inflammation; innate immunity; macrophage; macrophage memory; polarization