Histone deacetylase 3 is an epigenomic brake in macrophage alternative activation
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 activat...
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| Veröffentlicht in: | Genes & development 2011-12, Vol.25 (23), p.2480-2488 |
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| container_title | Genes & development |
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1101/gad.175950.111 |
| format | Article |
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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.</description><identifier>ISSN: 0890-9369</identifier><identifier>EISSN: 1549-5477</identifier><identifier>DOI: 10.1101/gad.175950.111</identifier><identifier>PMID: 22156208</identifier><language>eng</language><publisher>United States: Cold Spring Harbor Laboratory Press</publisher><subject>Acetylation ; Animals ; Epigenesis, Genetic ; Histone Deacetylases - genetics ; Histone Deacetylases - metabolism ; Interleukin-4 - genetics ; Interleukin-4 - metabolism ; Macrophage Activation - genetics ; Macrophages - immunology ; Macrophages - metabolism ; Mice ; Mice, Inbred Strains ; Pneumonia - enzymology ; Pneumonia - immunology ; Pneumonia - parasitology ; Research Paper ; Schistosoma mansoni ; Th2 Cells - immunology ; Th2 Cells - metabolism</subject><ispartof>Genes & development, 2011-12, Vol.25 (23), p.2480-2488</ispartof><rights>Copyright © 2011 by Cold Spring Harbor Laboratory Press 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c487t-a95eaa243136de2ab8e33f098b6e8e76cf089f7f508da82c6216a11491c81cac3</citedby><cites>FETCH-LOGICAL-c487t-a95eaa243136de2ab8e33f098b6e8e76cf089f7f508da82c6216a11491c81cac3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243058/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243058/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,724,777,781,882,27905,27906,53772,53774</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22156208$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mullican, Shannon E</creatorcontrib><creatorcontrib>Gaddis, Christine A</creatorcontrib><creatorcontrib>Alenghat, Theresa</creatorcontrib><creatorcontrib>Nair, Meera G</creatorcontrib><creatorcontrib>Giacomin, Paul R</creatorcontrib><creatorcontrib>Everett, Logan J</creatorcontrib><creatorcontrib>Feng, Dan</creatorcontrib><creatorcontrib>Steger, David J</creatorcontrib><creatorcontrib>Schug, Jonathan</creatorcontrib><creatorcontrib>Artis, David</creatorcontrib><creatorcontrib>Lazar, Mitchell A</creatorcontrib><title>Histone deacetylase 3 is an epigenomic brake in macrophage alternative activation</title><title>Genes & development</title><addtitle>Genes Dev</addtitle><description>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.</description><subject>Acetylation</subject><subject>Animals</subject><subject>Epigenesis, Genetic</subject><subject>Histone Deacetylases - genetics</subject><subject>Histone Deacetylases - metabolism</subject><subject>Interleukin-4 - genetics</subject><subject>Interleukin-4 - metabolism</subject><subject>Macrophage Activation - genetics</subject><subject>Macrophages - immunology</subject><subject>Macrophages - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred Strains</subject><subject>Pneumonia - enzymology</subject><subject>Pneumonia - immunology</subject><subject>Pneumonia - parasitology</subject><subject>Research Paper</subject><subject>Schistosoma mansoni</subject><subject>Th2 Cells - immunology</subject><subject>Th2 Cells - metabolism</subject><issn>0890-9369</issn><issn>1549-5477</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU1v2zAMhoViRZt-XHscdNvJmWhZsnQZMBTtUiBAUaA9C4xMp9psObOcAvn3VZAu2G47kYReviL5MHYDYg4g4OsamznUyqp9DSdsBqqyharq-hObCWNFYaW25-wipZ9CCC20PmPnZQlKl8LM2NMipGmIxBtCT9Ouw0Rc8pA4Rk6bsKY49MHz1Yi_iIfIe_TjsHnFNXHsJhojTuEt5z6HnA7xip222CW6_oiX7OX-7vl2USwffzzcfl8WvjL1VKBVhFhWEqRuqMSVISlbYc1Kk6Fa-zZP39atEqZBU3pdgkaAyoI34NHLS_bt4LvZrnpqPMVpxM5txtDjuHMDBvfvSwyvbj28OZk_Fcpkgy8fBuPwe0tpcn1InroOIw3b5Oz-lJUw8j-UYGWmobJyflDmI6U0UnucB4TbA3MZmDsAyzXkhs9_b3GU_yEk3wGfGZKt</recordid><startdate>20111201</startdate><enddate>20111201</enddate><creator>Mullican, Shannon E</creator><creator>Gaddis, Christine A</creator><creator>Alenghat, Theresa</creator><creator>Nair, Meera G</creator><creator>Giacomin, Paul R</creator><creator>Everett, Logan J</creator><creator>Feng, Dan</creator><creator>Steger, David J</creator><creator>Schug, Jonathan</creator><creator>Artis, David</creator><creator>Lazar, Mitchell A</creator><general>Cold Spring Harbor Laboratory Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20111201</creationdate><title>Histone deacetylase 3 is an epigenomic brake in macrophage alternative activation</title><author>Mullican, Shannon E ; 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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. 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| subjects | Acetylation Animals Epigenesis, Genetic Histone Deacetylases - genetics Histone Deacetylases - metabolism Interleukin-4 - genetics Interleukin-4 - metabolism Macrophage Activation - genetics Macrophages - immunology Macrophages - metabolism Mice Mice, Inbred Strains Pneumonia - enzymology Pneumonia - immunology Pneumonia - parasitology Research Paper Schistosoma mansoni Th2 Cells - immunology Th2 Cells - metabolism |
| title | Histone deacetylase 3 is an epigenomic brake in macrophage alternative activation |
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