1] Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy [2] IMS Laboratory, University of Bordeaux, 33607 Pessac, France [3].
1] Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy [2].
Nature. 2014 Jul 10;511(7508):184-90. doi: 10.1038/nature13323.
Disease tolerance is the ability of the host to reduce the effect of infection on host fitness. Analysis of disease tolerance pathways could provide new approaches for treating infections and other inflammatory diseases. Typically, an initial exposure to bacterial lipopolysaccharide (LPS) induces a state of refractoriness to further LPS challenge (endotoxin tolerance). We found that a first exposure of mice to LPS activated the ligand-operated transcription factor aryl hydrocarbon receptor (AhR) and the hepatic enzyme tryptophan 2,3-dioxygenase, which provided an activating ligand to the former, to downregulate early inflammatory gene expression. However, on LPS rechallenge, AhR engaged in long-term regulation of systemic inflammation only in the presence of indoleamine 2,3-dioxygenase 1 (IDO1). AhR-complex-associated Src kinase activity promoted IDO1 phosphorylation and signalling ability. The resulting endotoxin-tolerant state was found to protect mice against immunopathology in Gram-negative and Gram-positive infections, pointing to a role for AhR in contributing to host fitness.
疾病耐受力是宿主降低感染对宿主适应性影响的能力。分析疾病耐受力途径可为治疗感染和其他炎症性疾病提供新方法。通常，首次接触细菌脂多糖（LPS）会使机体对进一步的 LPS 挑战产生抵抗力（内毒素耐受）。我们发现，小鼠首次接触 LPS 会激活配体操纵的转录因子芳香烃受体（AhR）和肝脏酶色氨酸 2,3-双加氧酶，后者为前者提供激活配体，从而下调早期炎症基因表达。然而，在 LPS 再挑战时，只有在色氨酸 2,3-双加氧酶 1（IDO1）存在的情况下，AhR 才会参与系统性炎症的长期调节。AhR 复合物相关Src 激酶活性促进 IDO1 的磷酸化和信号转导能力。这种内毒素耐受状态可保护小鼠免受革兰氏阴性和革兰氏阳性感染引起的免疫病理损伤，表明 AhR 在宿主适应性中起作用。
