Dataset Information

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.

SUBMITTER: Mullican SE

PROVIDER: S-EPMC3243058 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Histone deacetylase 3 is an epigenomic brake in macrophage alternative activation.

Mullican Shannon E SE Gaddis Christine A CA Alenghat Theresa T Nair Meera G MG Giacomin Paul R PR Everett Logan J LJ Feng Dan D Steger David J DJ Schug Jonathan J Artis David D Lazar Mitchell A MA

Genes & development 20111201 23

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) displa ...[more]

PMID: 22156208

Similar Datasets

Project description:Background and purposeSepsis is a systemic inflammatory response accompanied by excessive production of inflammatory cytokines and cardiovascular dysfunction. Importantly, macrophage-derived pro-inflammatory agents play a key role in cardiovascular impairment in sepsis. Here we have investigated the effects of trimetazidine (TMZ) on pro-inflammatory responses of macrophages in endotoxin-induced myocardial dysfunction.Experimental approachMice pretreated with TMZ were injected i.p. with LPS and cardiac function evaluated. Levels of macrophage infiltration, macrophage inflammatory response and cardiomyocyte apoptosis were measured using immunohistochemical staining, elisa, real-time RT-PCR, Western blot, TUNEL and flow cytometry assays.Key resultsPretreatment with TMZ prevented LPS-induced myocardial dysfunction and apoptosis. TMZ also lowered levels of pro-inflammatory cytokines in serum and cardiac tissue and myocardial macrophage infiltration. Bone marrow transplantation indicated that TMZ alleviated LPS-induced myocardial dysfunction via decreasing macrophage infiltration. TMZ reduced expression of pro-inflammatory cytokines in LPS-stimulated cardiac and peritoneal macrophages. Co-culture of TMZ-pretreated macrophages with cardiomyocytes and conditioned media from TMZ-pretreated macrophages both decreased LPS-induced cardiomyocyte apoptosis. The anti-apoptosis effects of TMZ resulted from decrease of pro-inflammatory cytokines, partly due to normalizing the sirtuin 1 (Sirt1)/AMP-activated protein kinase (AMPK)/Nrf2/haem oxygenase-1 and Sirt1/PPARα pathways in macrophages. Cytokine secretion was also regulated by ROS, which were attenuated by TMZ via activation of Sirt1, AMPK and PPARα.Conclusions and implicationsTMZ protected against LPS-induced myocardial dysfunction and apoptosis, accompanied by inhibition of macrophage pro-inflammatory responses. Our studies suggest that TMZ might represent a novel therapeutic agent to prevent and treat sepsis-induced myocardial dysfunction.

Dataset Information

Histone deacetylase 3 is an epigenomic brake in macrophage alternative activation.

Publications

Histone deacetylase 3 is an epigenomic brake in macrophage alternative activation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets