Histone deacetylase 3 is an epigenomic brake in macrophage alternative activation
Mullican, Shannon E., Gaddis, Christine A., Alenghat, Theresa, Nair, Meera G., Giacomin, Paul R., Everett, Logan J., Feng, Dan, Steger, David J., Schug, Jonathan, Artis, David, and Lazar, Mitchell A. (2011) Histone deacetylase 3 is an epigenomic brake in macrophage alternative activation. Genes & Development, 25 (23). pp. 2480-2488.
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Macrophages, a key cellular component of inflammation, become functionally polarized in a signal- and context-specific manner. Th2 cytokines such as interleukin 4 (IL-4) polarize macrophages to a state of alternative activation that limits inflammation and promotes wound healing. Alternative activation is mediated by a transcriptional program that is influenced by epigenomic modifications, including histone acetylation. Here we report that macrophages lacking histone deacetylase 3 (HDAC3) display a polarization phenotype similar to IL-4-induced alternative activation and, furthermore, are hyperresponsive to IL-4 stimulation. Throughout the macrophage genome, HDAC3 deacetylates histone tails at regulatory regions, leading to repression of many IL-4-regulated genes characteristic of alternative activation. Following exposure to Schistosoma mansoni eggs, a model of Th2 cytokine-mediated disease that is limited by alternative activation, pulmonary inflammation was ameliorated in mice lacking HDAC3 in macrophages. Thus, HDAC3 functions in alternative activation as a brake whose release could be of benefit in the treatment of multiple inflammatory diseases.
|Item Type:||Article (Refereed Research - C1)|
|Keywords:||HDAC3; macrophage; epigenomic|
Supplemental material is available for this article.
|Date Deposited:||22 Jun 2012 00:00|
|FoR Codes:||06 BIOLOGICAL SCIENCES > 0604 Genetics > 060406 Genetic Immunology @ 100%|
|SEO Codes:||92 HEALTH > 9299 Other Health > 929999 Health not elsewhere classified @ 100%|