Microbial challenges, such as widespread bacterial infection, induce endotoxin tolerance. This state of hyporesponsiveness 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 TLR4 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 on the first encounter with LPS. This is evidence of a crucial role for 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 assess the pathological relevance of the JAK2 pathway in monocytes from patients with sepsis.

中文翻译：

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第一次遇到细菌抗原时，JAK2-STAT途径表观遗传调控耐受基因

诸如广泛的细菌感染之类的微生物挑战会诱导内毒素耐受性。对后续感染的反应低下状态主要表现为单核细胞和巨噬细胞。内毒素耐受性通常在败血症发作后获得。在这项研究中，我们调查了体外耐受性获得过程中DNA甲基化的变化。我们确定了一组TET2介导的去甲基化事件，这些事件对通行费样受体（TLR）2和TLR4刺激具有特异性。脂多糖（LPS）特定的脱甲基发生在静止单核细胞中难以接近的基因组位点，伴随着许多炎症相关基因的转录激活，并且它们丰富了多个信号转导子和转录激活子（STAT）家族的结合基序。成员。确实，STAT1 STAT3和STAT5是JAK2途径的元素，与内毒素耐受性的获得相关联被磷酸化。对JAK2途径的抑制会损害首次与LPS接触时耐受的基因的激活。这证明了该途径在确定这些基因对细菌抗原的初始反应中的关键作用，并提供了药理学靶标，以防止加剧的反应，从而在随后的挑战中实现调节的反应。最后，我们评估败血症患者单核细胞中JAK2途径的病理相关性。这证明了该途径在确定这些基因对细菌抗原的初始反应中的关键作用，并提供了药理学靶标，以防止加剧的反应，从而在随后的挑战中实现调节的反应。最后，我们评估败血症患者单核细胞中JAK2途径的病理相关性。这证明了该途径在确定这些基因对细菌抗原的初始反应中的关键作用，并提供了药理学靶标，以防止加剧的反应，从而在随后的挑战中实现调节的反应。最后，我们评估败血症患者单核细胞中JAK2途径的病理相关性。