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. 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 () and Paolo Puccetti ()
Additional contact information
Alban Bessede: University of Perugia, 06132 Perugia, Italy
Marco Gargaro: University of Perugia, 06132 Perugia, Italy
Maria T. Pallotta: University of Perugia, 06132 Perugia, Italy
Davide Matino: University of Perugia, 06132 Perugia, Italy
Giuseppe Servillo: University of Perugia, 06132 Perugia, Italy
Cinzia Brunacci: University of Perugia, 06132 Perugia, Italy
Silvio Bicciato: Center for Genome Research, University of Modena and Reggio Emilia, 41125 Modena, Italy
Emilia M. C. Mazza: Center for Genome Research, University of Modena and Reggio Emilia, 41125 Modena, Italy
Antonio Macchiarulo: University of Perugia, 06123 Perugia, Italy
Carmine Vacca: University of Perugia, 06132 Perugia, Italy
Rossana Iannitti: University of Perugia, 06132 Perugia, Italy
Luciana Tissi: University of Perugia, 06132 Perugia, Italy
Claudia Volpi: University of Perugia, 06132 Perugia, Italy
Maria L. Belladonna: University of Perugia, 06132 Perugia, Italy
Ciriana Orabona: University of Perugia, 06132 Perugia, Italy
Roberta Bianchi: University of Perugia, 06132 Perugia, Italy
Tobias V. Lanz: Experimental Neuroimmunology Unit, German Cancer Research Center, 69120 Heidelberg, Germany
Michael Platten: Experimental Neuroimmunology Unit, German Cancer Research Center, 69120 Heidelberg, Germany
Maria A. Della Fazia: University of Perugia, 06132 Perugia, Italy
Danilo Piobbico: University of Perugia, 06132 Perugia, Italy
Teresa Zelante: University of Perugia, 06132 Perugia, Italy
Hiroshi Funakoshi: Center for Advanced Research and Education, Asahikawa Medical University, 078-8510 Asahikawa, Japan
Toshikazu Nakamura: Center for Advanced Science and Innovation, Osaka University, 565-0871 Osaka, Japan
David Gilot: CNRS UMR6290, Institut de Génétique et Développement de Rennes, Université de Rennes 1, 35043 Rennes, France
Michael S. Denison: University of California
Gilles J. Guillemin: Australian School of Advanced Medicine (ASAM), Macquarie University, 2109 New South Wales, Australia
James B. DuHadaway: Lankenau Institute for Medical Research
George C. Prendergast: Lankenau Institute for Medical Research
Richard Metz: New Link Genetics Corporation
Michel Geffard: IMS Laboratory, University of Bordeaux, 33607 Pessac, France
Louis Boon: Bioceros, 3584 Utrecht, The Netherlands
Matteo Pirro: University of Perugia, 06132 Perugia, Italy
Alfonso Iorio: McMaster University, Ontario L8S 4K1, Canada
Bernard Veyret: IMS Laboratory, University of Bordeaux, 33607 Pessac, France
Luigina Romani: University of Perugia, 06132 Perugia, Italy
Ursula Grohmann: University of Perugia, 06132 Perugia, Italy
Francesca Fallarino: University of Perugia, 06132 Perugia, Italy
Paolo Puccetti: University of Perugia, 06132 Perugia, Italy

Nature, 2014, vol. 511, issue 7508, 184-190

Abstract: Abstract 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.

Date: 2014
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DOI: 10.1038/nature13323

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