GSE159249
The JAK2-STAT pathway epigenetically regulates tolerized genes during the first encounter to bacterial antigens [RNA-seq]
Microbial challenges, such as widespread bacterial infection, induce endotoxin tolerance. This state of hypo-responsiveness to subsequent infections is mainly displayed by monocytes and macrophages. Endotoxin tolerance is generally acquired following a septic episode. In this study, we investigated DNA methylation changes during the acquisition of in vitro tolerance. We identified a set of TET2-mediated demethylation events that are specific to toll like receptor (TLR) 2 and 4 stimulation. Lipopolysaccharide (LPS)-specific demethylation occurs at genomic sites that have low accessibility in quiescent monocytes, concomitantly with the transcriptional activation of many inflammation-related genes, and they are enriched in binding motifs for several signal transducer and activator of transcription (STAT) family members. Indeed, STAT1, STAT3 and STAT5, elements of the JAK2 pathway, are phosphorylated in association with the acquisition of endotoxin tolerance. Inhibition of the JAK2 pathway impairs the activation of tolerized genes at the first encounter with LPS. This supports a crucial role of this pathway in determining the initial response of these genes to bacterial antigens and provides a pharmacological target to prevent exacerbated responses, allowing regulated responses upon subsequent challenges. Finally, we prove the pathological relevance of the JAK2 pathway in monocytes from patients with sepsis. Overall design: RNA were isolated from 12 samples from 3 different donors. 4 conditions: non-cultured monocytes, non-treated monocytes, LPS monocytes and P3C monocytes