NF-κB-dependent repression of Sox18 transcription factor requires the epigenetic regulators histone deacetylases 1 and 2 in acute lung injury

Abstract

In acute lung injury (ALI), the NF-κB-mediated downregulation of Sox18 gene expression leads to the disruption of the pulmonary endothelial barrier. Previous studies have suggested that the action of NF-κB as a transcriptional repressor also requires the action of class I histone deacetylases (HDACs). Thus, the purpose of this study was to investigate and further delineate the mechanism of Sox18 repression during lipopolysaccharide (LPS) induced ALI. Using selective inhibitors and specific siRNA-driven depletion of HDACs 1-3 in human lung microvascular endothelial cells (HLMVEC) we were able to demonstrate a critical role for HDACs 1 and 2 in the LPS-mediated repression of Sox18 gene expression and the loss of endothelial monolayer integrity. Moreover, our data demonstrate that HDAC1 associates with a transcription-repressive complex within the NF-κB-binding site of Sox18 promoter. Further, we were able to show that the selective inhibitor of HDAC1, tacedinaline, significantly reduced the endothelial permeability and injury associated with LPS challenge in the mouse lung. Taken together, our data demonstrate, for the first time, that transcription repressors HDACs 1 and 2 are involved in pathological mechanism of ALI and can be considered as therapeutic targets.

Loss of SOX18/CLAUDIN5 disrupts the pulmonary endothelial barrier in ventilator-induced lung injury

“…These findings suggest that SOX18 not only reduces lung edema by maintaining barrier function but also has anti-inflammatory activity by inhibiting the NF-κB-induced lung inflammatory response. We recently showed that NF-κB could repress SOX18 transcription via an HDAC-mediated epigenetic regulation ( Gross et al, 2018 ; Zemskov et al, 2022 ). Our current findings suggest that SOX18 attenuates NF-κB activity by attenuating the phosphorylation of the NF-κB subunit p65 at S536.…”

Zinc-Dependent Histone Deacetylases in Lung Endothelial Pathobiology

“…However, the role of specific HDAC subtypes remains incompletely defined and somewhat contradictory. For example, a recent study demonstrated that nuclear class I HDACs-HDAC1 and HDAC2, but not nuclear/cytoplasmic HDAC3-are involved in lung microvascular EC barrier dysfunction induced by lipopolysaccharide (LPS) via the suppression of Sox18 gene expression [109]. However, another study demonstrated that the pharmacological inhibition of HDAC1, HDAC2, and HDAC3 leads to EC barrier dysfunction in mice and increased lung vascular leak by suppression of EC Roundabout4 (Robo4) receptor expression [110].…”

“…The nuclear HDAC1 and HDAC2 participation in the endothelial barrier compromise in vitro and lung injury in an LPS murine model was recently evaluated [109]. Selective inhibition of HDAC1 and HDAC2, but not HDAC3, attenuates LPS-induced hyperpermeability in HLMVECs, likely through the preservation of Sox 18 expression, which LPS downregulates.…”

Epigenetic mechanisms of Immune remodeling in sepsis: targeting histone modification

“…As sepsis progresses, gene silencing and chromatin structural remodeling caused by HADCs trigger the alternation of cellular expression files, which are assumed to be associated with immunosuppression in late sepsis [ 46 , 51 ]. Classical histone deacetylases, including HDAC1-8, act as players in the progression of sepsis and inflammation and are involved in the multi-organ dysfunction of sepsis [ 46 , 49 , 52 , 53 ]. These deacetylases regulate the expression of inflammatory genes on immune cells or cellular apoptosis in polymicrobial CLP septic models or LPS-mediated endotoxemia models [ 46 , 53 ].…”