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 PiobbicoTeresa Zelante, Hiroshi Funakoshi, Toshikazu Nakamura, David Gilot, Michael S. Denison, Gilles J. Guillemin, James B. Duhadaway, George C. Prendergast, Richard Metz, Michel Geffard, Louis Boon, Matteo Pirro, Alfonso Iorio, Bernard Veyret, Luigina Romani, Ursula Grohmann, Francesca Fallarino, Paolo Puccetti*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    497 Citations (Scopus)


    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.

    Original languageEnglish
    Pages (from-to)184-190
    Number of pages7
    Issue number7508
    Publication statusPublished - 2014


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