IRAK-M regulates chromatin remodeling in lung macrophages during experimental sepsis

Kenneth Lyn-Kew, Eric Rich, Xianying Zeng, Haitao Wen, Steven L. Kunkel, Michael W. Newstead, Urvashi Bhan, Theodore J. Standiford

Research output: Contribution to journalArticle

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Abstract

Sepsis results in a profound state of immunosuppression, which is temporally associated with impaired leukocyte function. The mechanism of leukocyte reprogramming in sepsis is incompletely understood. In this study, we explored mechanisms contributing to dysregulated inflammatory cytokine expression by pulmonary macrophages during experimental sepsis. Pulmonary macrophages (PM) recovered from the lungs of mice undergoing cecal ligation and puncture (CLP) display transiently reduced expression of some, but not all innate genes in response to LPS. Impaired expression of TNF-a and iNOS was associated with reduced acetylation and methylation of specific histones (AcH4 and H3K4me3) and reduced binding of RNA polymerase II to the promoters of these genes. Transient impairment in LPS-induced cytokine responses in septic PM temporally correlated with induction of IRAK-M mRNA and protein, which occurred in a MyD88-dependent fashion. PM isolated from IRAK-M-/- mice were largely refractory to CLP-induced impairment in cytokine expression, chromatin remodeling, recruitment of RNA polymerase II, and induction of histone deacetylase-2 observed during sepsis. Our findings indicate that systemic sepsis induces epigenetic silencing of cytokine gene expression in lung macrophages, and IRAK-M appears to be a critical mediator of this response.

Original languageEnglish (US)
Article numbere11145
JournalPloS one
Volume5
Issue number6
DOIs
StatePublished - Aug 11 2010

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Chromatin Assembly and Disassembly
Macrophages
Chromatin
chromatin
Alveolar Macrophages
Sepsis
macrophages
lungs
Cytokines
Lung
RNA Polymerase II
cytokines
Histone Deacetylase 2
Punctures
Genes
Ligation
DNA-directed RNA polymerase
Leukocytes
Acetylation
Methylation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Lyn-Kew, K., Rich, E., Zeng, X., Wen, H., Kunkel, S. L., Newstead, M. W., ... Standiford, T. J. (2010). IRAK-M regulates chromatin remodeling in lung macrophages during experimental sepsis. PloS one, 5(6), [e11145]. https://doi.org/10.1371/journal.pone.0011145

IRAK-M regulates chromatin remodeling in lung macrophages during experimental sepsis. / Lyn-Kew, Kenneth; Rich, Eric; Zeng, Xianying; Wen, Haitao; Kunkel, Steven L.; Newstead, Michael W.; Bhan, Urvashi; Standiford, Theodore J.

In: PloS one, Vol. 5, No. 6, e11145, 11.08.2010.

Research output: Contribution to journalArticle

Lyn-Kew, K, Rich, E, Zeng, X, Wen, H, Kunkel, SL, Newstead, MW, Bhan, U & Standiford, TJ 2010, 'IRAK-M regulates chromatin remodeling in lung macrophages during experimental sepsis', PloS one, vol. 5, no. 6, e11145. https://doi.org/10.1371/journal.pone.0011145
Lyn-Kew K, Rich E, Zeng X, Wen H, Kunkel SL, Newstead MW et al. IRAK-M regulates chromatin remodeling in lung macrophages during experimental sepsis. PloS one. 2010 Aug 11;5(6). e11145. https://doi.org/10.1371/journal.pone.0011145
Lyn-Kew, Kenneth ; Rich, Eric ; Zeng, Xianying ; Wen, Haitao ; Kunkel, Steven L. ; Newstead, Michael W. ; Bhan, Urvashi ; Standiford, Theodore J. / IRAK-M regulates chromatin remodeling in lung macrophages during experimental sepsis. In: PloS one. 2010 ; Vol. 5, No. 6.
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