Inhibiting KDM6A Demethylase Represses Long Non-Coding RNA Hotairm1 Transcription in MDSC During Sepsis.

Isatou Bah,Mohamed El Gazzar,Charles E Mccall,Dima Youssef,Zhi Q Yao

doi:10.3389/fimmu.2022.823660

Isatou Bah, Mohamed El Gazzar + Show 3 more

Open Access

https://doi.org/10.3389/fimmu.2022.823660

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Abstract

Myeloid-derived suppressor cells (MDSCs) prolong sepsis by promoting immunosuppression. We reported that sepsis MDSC development requires long non-coding RNA Hotairm1 interactions with S100A9. Using a mouse model that simulates the immunobiology of sepsis, we find that histone demethylase KDM6A promotes Hotairm1 transcription by demethylating transcription repression H3K27me3 histone mark. We show that chemical targeting of KDM6A by GSK-J4 represses Hotairm1 transcription, which coincides with decreases in transcription activation H3K4me3 histone mark and transcription factor PU.1 binding to the Hotairm1 promoter. We further show that immunosuppressive IL-10 cytokine promotes KDM6A binding at the Hotairm1 promoter. IL-10 knockdown repletes H3K27me3 and reduces Hotairm1 transcription. GSK-J4 treatment also relocalizes nuclear S100A9 protein to the cytosol. To support translation to human sepsis, we demonstrate that inhibiting H3K27me3 demethylation by KDM6A ex vivo in MDSCs from patients with protracted sepsis decreases Hotairm1 transcription. These findings suggest that epigenetic targeting of MDSCs in human sepsis might resolve post-sepsis immunosuppression and improve sepsis survival.

Highlights

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection and a leading cause of death and critical illness [1, 2]
Chromatin Immunoprecipitation (ChIP) analysis of Hotairm1 promoter showed that KDM6A binding was significantly higher in Myeloid-derived suppressor cells (MDSCs) from mice with later sepsis compared with early sepsis
MDSCs from mice with later sepsis, which exhibit the most decrease in H3K27me3 and increase in KDM6A binding, were incubated with DMSO or increasing concentrations of GSK-J4 for 12 h

Summary

Introduction

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection and a leading cause of death and critical illness [1, 2]. Myeloid-derived suppressor cells (MDSCs) are pathologically activated neutrophils and monocytes that emerge from myeloid progenitors during aberrant stimulation of myeloid progenitors/ precursors with cytokines and growth factors, and which enter sites of infection and inflammation [10,11,12]. MDSCs continue to increase in blood, spleen, and bone marrow in mice and humans with sepsis, contributing to the protracted sepsis phenotype [13,14,15,16], called persistent inflammation, immunosuppression, and catabolism syndrome (PICS) [9, 15]. We reported that levels of lncRNA Hotairm in MDSCs increase in mice with later/protracted sepsis [18]. Hotairm transfers cytosolic S100A9 to the nucleus in MDSCs, at least in part, to drive MDSC immunosuppressive effects

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