Histone deacetylase 3 is an epigenomic brake in macrophage alternative activation
- Shannon E. Mullican1,2,3,
- Christine A. Gaddis1,2,3,
- Theresa Alenghat1,2,3,4,
- Meera G. Nair4,5,6,
- Paul R. Giacomin4,5,6,
- Logan J. Everett1,2,3,
- Dan Feng1,2,3,
- David J. Steger1,2,3,
- Jonathan Schug1,2,3,
- David Artis4,5,6 and
- Mitchell A. Lazar1,2,3,7
- 1Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine,
- 2Department of Genetics,
- 3The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 4Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania 19104, USA;
- 5Department of Microbiology,
- 6Institute for Immunology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Abstract
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.
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Footnotes
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↵7 Corresponding author.
E-mail lazar{at}mail.med.upenn.edu.
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.175950.111.
- Received August 17, 2011.
- Accepted October 24, 2011.
- Copyright © 2011 by Cold Spring Harbor Laboratory Press