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 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.
Lyn-Kew
Kenneth
K
Division of Pulmonary and Critical Care Medicine, Department of Medicine, The University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
Rich
Eric
E
Zeng
Xianying
X
Wen
Haitao
H
Kunkel
Steven L
SL
Newstead
Michael W
MW
Bhan
Urvashi
U
Standiford
Theodore J
TJ
D000818:Animals; D001483:Base Sequence; D042002:Chromatin Assembly and Disassembly / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000502:physiology*; D008168:Lung / Q000473:pathology*; D008264:Macrophages / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000473:pathology / Q000503:physiopathology*
D017931:DNA Primers; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse