IRAK-M regulates chromatin remodeling in lung macrophages during experimental sepsis.
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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2010-06-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2886833?pdf=render |
| _version_ | 1819205719304437760 |
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| author | Kenneth Lyn-Kew Eric Rich Xianying Zeng Haitao Wen Steven L Kunkel Michael W Newstead Urvashi Bhan Theodore J Standiford |
| author_facet | Kenneth Lyn-Kew Eric Rich Xianying Zeng Haitao Wen Steven L Kunkel Michael W Newstead Urvashi Bhan Theodore J Standiford |
| author_sort | Kenneth Lyn-Kew |
| collection | DOAJ |
| description | 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-alpha 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. |
| first_indexed | 2024-12-23T04:56:10Z |
| format | Article |
| id | doaj.art-0f0a89d0a02346d0ab9b0bd5ab2d56a0 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-23T04:56:10Z |
| publishDate | 2010-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-0f0a89d0a02346d0ab9b0bd5ab2d56a02022-12-21T17:59:20ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-06-0156e1114510.1371/journal.pone.0011145IRAK-M regulates chromatin remodeling in lung macrophages during experimental sepsis.Kenneth Lyn-KewEric RichXianying ZengHaitao WenSteven L KunkelMichael W NewsteadUrvashi BhanTheodore J StandifordSepsis 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-alpha 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.http://europepmc.org/articles/PMC2886833?pdf=render |
| spellingShingle | Kenneth Lyn-Kew Eric Rich Xianying Zeng Haitao Wen Steven L Kunkel Michael W Newstead Urvashi Bhan Theodore J Standiford IRAK-M regulates chromatin remodeling in lung macrophages during experimental sepsis. PLoS ONE |
| title | IRAK-M regulates chromatin remodeling in lung macrophages during experimental sepsis. |
| title_full | IRAK-M regulates chromatin remodeling in lung macrophages during experimental sepsis. |
| title_fullStr | IRAK-M regulates chromatin remodeling in lung macrophages during experimental sepsis. |
| title_full_unstemmed | IRAK-M regulates chromatin remodeling in lung macrophages during experimental sepsis. |
| title_short | IRAK-M regulates chromatin remodeling in lung macrophages during experimental sepsis. |
| title_sort | irak m regulates chromatin remodeling in lung macrophages during experimental sepsis |
| url | http://europepmc.org/articles/PMC2886833?pdf=render |
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