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内毒素耐受被发现与色氨酸代谢有关

摘要 : 由意大利佩鲁贾大学领导的一个国际研究组揭示寄主产生细菌内毒素耐受的分子机制。相关文章发表于2014年7月9日的《Nature》杂志上。

内毒素耐受是先天免疫的一个方面,它是指之前如果接触过一种细菌内毒素(或脂多糖)的话,那么寄主对之后接触这种内毒素的反应就会降低。尽管人们最近对这一效应又产生了兴趣,但对其深层机制却很不了解。

这篇论文显示,内毒素耐受的形成取决于通过代谢酶“吲哚胺-2,3-加双氧酶-1”(IDO1)和“色氨酸-2,3-加双氧酶”(TDO2)的依次参与所发生的色氨酸代谢。这会导致犬尿氨酸的生成,后者会激活“芳香烃受体”(AhR)。

内毒素所带来的主要挑战由AhR、TDO2和白介素控制,而持续的耐受则需要AhR、IDO1和细胞因子 TGF-β,从而使得在几乎不产生任何免疫病理反应的情况下能够将病原体清除。

原文摘要:

Aryl hydrocarbon receptor control of a disease tolerance defence pathway

Alban Bessede, Marco Gargaro, Maria T. Pallotta, Davide Matino, Giuseppe Servillo,Cinzia Brunacci, Silvio Bicciato, Emilia M. C. Mazza, Antonio Macchiarulo, Carmine Vacca,Rossana Iannitti, Luciana Tissi, Claudia Volpi, Maria L. Belladonna, Ciriana Orabona,Roberta Bianchi, Tobias V. Lanz, Michael Platten, Maria A. Della Fazia, Danilo Piobbico,Teresa Zelante, Hiroshi Funakoshi, Toshikazu Nakamura, David Gilot, Michael S. Denisonet al.

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.

对应Nature杂志: 2014年7月10日Nature杂志精选

来源: Nature中文 浏览次数:78

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