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Shock drives a STAT3 and JunB-mediated coordinated transcriptional and DNA methylation response in the endothelium.

Ramon Bossardi RamosNina MartinoDareen ChuyShuhan LuMei Xing G ZuoUma BalasubramanianIria Di John PortelaPeter A VincentAlejandro Pablo Adam
Published in: Journal of cell science (2023)
Endothelial dysfunction is a critical factor in promoting organ failure during septic shock. However, the underlying mechanisms are unknown. Here, we show that kidney injury after LPS leads to strong endothelial transcriptional and epigenetic responses. Further, SOCS3 loss leads to an aggravation of the responses, demonstrating a causal role for the STAT3/SOCS3 signaling axis in the acute endothelial response to LPS. Experiments in cultured endothelial cells demonstrate that IL-6 mediates this response. Furthermore, bioinformatics analysis of in vivo and in vitro transcriptomics and epigenetics suggests a role for STAT, AP1, and IRF transcription factors. Knockdown of STAT3 or the AP1 member JunB partially prevents the changes in gene expression, demonstrating a role for these transcription factors. In conclusion, endothelial cells respond with a coordinated response that depends on overactivated IL-6 signaling via STAT3, JunB, and possibly other transcription factors. Our findings provide evidence for a critical role of IL-6 signaling in regulating shock-induced epigenetic changes and sustained endothelial activation, offering a new therapeutic target to limit vascular dysfunction.
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