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;Lazar, Mitchell A.

Paul Giacomin

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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1549-5477

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Cold Spring Harbor Laboratory Press

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DOI

10.1101/gad.175950.111