title: Histone deacetylase 3 is an epigenomic brake in macrophage alternative activation.
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.
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Mullican
authors.forename: Christine A
authors.initials: CA
authors.lastname: Gaddis
authors.forename: Theresa
authors.initials: T
authors.lastname: Alenghat
authors.forename: Meera G
authors.initials: MG
authors.lastname: Nair
authors.forename: Paul R
authors.initials: PR
authors.lastname: Giacomin
authors.forename: Logan J
authors.initials: LJ
authors.lastname: Everett
authors.forename: Dan
authors.initials: D
authors.lastname: Feng
authors.forename: David J
authors.initials: DJ
authors.lastname: Steger
authors.forename: Jonathan
authors.initials: J
authors.lastname: Schug
authors.forename: David
authors.initials: D
authors.lastname: Artis
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
mesh_terms: D000818:Animals; D044127:Epigenesis, Genetic; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D008262:Macrophage Activation / Q000235:genetics*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D011014:Pneumonia / Q000201:enzymology / Q000276:immunology / Q000469:parasitology; D012550:Schistosoma mansoni; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D000099186:Histone Deacetylase 3
chemical_list: D006655:Histone Deacetylases; D015847:Interleukin-4; D000099186:Histone Deacetylase 3