Epigenetic regulation of the alternatively activated macrophage phenotype

Makoto Ishii, Haitao Wen, Callie A.S. Corsa, Tianju Liu, Ana L. Coelho, Ronald M. Allen, William F. Carson IV, Karen A. Cavassani, Xiangzhi Li, Nicholas W. Lukacs, Cory M. Hogaboam, Yali Dou, Steven L. Kunkel

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263 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3244-3254
Number of pages11
JournalBlood
Volume114
Issue number15
DOIs
Publication statusPublished - 2009 Nov 19
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Ishii, M., Wen, H., Corsa, C. A. S., Liu, T., Coelho, A. L., Allen, R. M., Carson IV, W. F., Cavassani, K. A., Li, X., Lukacs, N. W., Hogaboam, C. M., Dou, Y., & Kunkel, S. L. (2009). Epigenetic regulation of the alternatively activated macrophage phenotype. Blood, 114(15), 3244-3254. https://doi.org/10.1182/blood-2009-04-217620