Epigenetic regulation of the alternatively activated macrophage phenotype.
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.
Ishii
Makoto
M
Immunology Program, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
Wen
Haitao
H
Corsa
Callie A S
CA
Liu
Tianju
T
Coelho
Ana L
AL
Allen
Ronald M
RM
Carson
William F
WF
Cavassani
Karen A
KA
Li
Xiangzhi
X
Lukacs
Nicholas W
NW
Hogaboam
Cory M
CM
Dou
Yali
Y
Kunkel
Steven L
SL
D000818:Animals; D042002:Chromatin Assembly and Disassembly / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000276:immunology*; D005260:Female; D005819:Genetic Markers / Q000235:genetics / Q000276:immunology; D006657:Histones / Q000235:genetics / Q000276:immunology; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D056484:Jumonji Domain-Containing Histone Demethylases; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D008745:Methylation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000276:immunology; D012550:Schistosoma mansoni / Q000276:immunology*; D012555:Schistosomiasis mansoni / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D015533:Transcriptional Activation / Q000235:genetics / Q000276:immunology
D005819:Genetic Markers; D006657:Histones; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015847:Interleukin-4; D056484:Jumonji Domain-Containing Histone Demethylases; C523761:Kdm6b protein, mouse; D010089:Oxidoreductases, N-Demethylating