IRAK-M Regulates Chromatin Remodeling in Lung Macrophages during Experimental Sepsis

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-α 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.

Immune Cell Dysfunction as a Consequence of Severe Sepsis

“…While the data concerning epigenetic reprogramming in macrophages is less robust in regards to long-term immunosuppression, modulations in histone modifications can be observed in macrophages following the onset of severe sepsis, and these modulations affect proinflammatory responses by these cells. For example, macrophages recovered from experimental models of severe sepsis exhibit increased levels of methylation at lysine 9 of histone 3 (H3K9, repressive) at the promoter region of both IL-1 and TNFα, resulting in decreased production of both inflammatory mediators (Lyn-Kew et al, 2010). This increase in repressive histone methylation appears to be a mechanism whereby the immune system is attempting to limit proinflammatory cytokine production; however, as both of these cytokines are critical for immunity against bacteria, their decreased production by macrophages can leave the immune system less able to properly respond to secondary infections.…”

Molecular biology of oncogenic inflammatory processes. I. Non-oncogenic and oncogenic pathogens, intrinsic inflammatory reactions without pathogens, and microRNA/DNA interactions (Review)

“…Immature dendritic cells (DCs) are often tolerogenic. The presence of CD123 + plasmacytoid DCs in breast cancer tissue is associated with poor prognosis (13).…”

“…When TLR4 recognizes LPS endotoxin, it signals through MyD88/IL1 to induce NFκB and the MAPK pathway. Polymorphism of the TLR4 gene may result in defective signaling, lack of defensive reactions and consequentially severe direct tissue damage by the endotoxin (13).…”

“…The cognate receptors of HMBAB proteins are the RAGE (receptors for advanced glycation end products, glycation, nonenzymatic glycolyzation), or TLR2, TLR4. These receptors generate NFκB, Eselectins and insulinlike growth factor and/or its receptor, IGFR (selectins are ligands to sialylated cell surface carbohydrates) (13).…”

“…At lysine (K) 4 of activator histone 3, triple methylation (me3) occurs (H3K4me3) and results in silenced posttrans lational modifications. At lysine (K) 27 of suppressor histone 3, triple methylation (me3) occurs (H3K27me3) and results in upregulated posttranslational modifications (13). Endotoxin (LPS) stimulated TLR4 activates myeloid differentiation factor 88, the scaffold protein (MyD88), IL1β, IL6, IL12 and TNFα.…”