title: Aryl hydrocarbon receptor control of a disease tolerance defence pathway.
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.
authors.affiliation: 1] Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy [2] IMS Laboratory, University of Bordeaux, 33607 Pessac, France [3].
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authors.initials: A
authors.lastname: Bessede
authors.affiliation: 1] Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy [2].
authors.forename: Marco
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authors.lastname: Gargaro
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Pallotta
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Davide
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authors.lastname: Matino
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Giuseppe
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authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Cinzia
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authors.affiliation: Center for Genome Research, University of Modena and Reggio Emilia, 41125 Modena, Italy.
authors.forename: Silvio
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authors.affiliation: Center for Genome Research, University of Modena and Reggio Emilia, 41125 Modena, Italy.
authors.forename: Emilia M C
authors.initials: EM
authors.lastname: Mazza
authors.affiliation: Department of Chemistry and Technology of Drugs, University of Perugia, 06123 Perugia, Italy.
authors.forename: Antonio
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authors.lastname: Macchiarulo
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Carmine
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authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Rossana
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authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Luciana
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authors.lastname: Tissi
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Claudia
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authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Belladonna
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Ciriana
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authors.lastname: Orabona
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Roberta
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authors.lastname: Bianchi
authors.affiliation: 1] Experimental Neuroimmunology Unit, German Cancer Research Center, 69120 Heidelberg, Germany [2] Department of Neurooncology, University Hospital, 69120 Heidelberg, Germany.
authors.forename: Tobias V
authors.initials: TV
authors.lastname: Lanz
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authors.lastname: Platten
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
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authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Danilo
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authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Teresa
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authors.lastname: Zelante
authors.affiliation: Center for Advanced Research and Education, Asahikawa Medical University, 078-8510 Asahikawa, Japan.
authors.forename: Hiroshi
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authors.lastname: Funakoshi
authors.affiliation: Kringle Pharma Joint Research Division for Regenerative Drug Discovery, Center for Advanced Science and Innovation, Osaka University, 565-0871 Osaka, Japan.
authors.forename: Toshikazu
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authors.lastname: Nakamura
authors.affiliation: CNRS UMR6290, Institut de Génétique et Développement de Rennes, Université de Rennes 1, 35043 Rennes, France.
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authors.affiliation: Department of Environmental Toxicology, University of California, Davis, 95616 California, USA.
authors.forename: Michael S
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authors.affiliation: Australian School of Advanced Medicine (ASAM), Macquarie University, 2109 New South Wales, Australia.
authors.forename: Gilles J
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authors.lastname: Guillemin
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, 19096 Pennsylvania, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: DuHadaway
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, 19096 Pennsylvania, USA.
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authors.initials: GC
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authors.affiliation: New Link Genetics Corporation, Ames, 50010 Iowa, USA.
authors.forename: Richard
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authors.lastname: Metz
authors.affiliation: IMS Laboratory, University of Bordeaux, 33607 Pessac, France.
authors.forename: Michel
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authors.lastname: Geffard
authors.affiliation: Bioceros, 3584 Utrecht, The Netherlands.
authors.forename: Louis
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authors.lastname: Boon
authors.affiliation: Department of Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Matteo
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authors.affiliation: Department of Clinical Epidemiology & Biostatistics, McMaster University, Ontario L8S 4K1, Canada.
authors.forename: Alfonso
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authors.lastname: Iorio
authors.affiliation: IMS Laboratory, University of Bordeaux, 33607 Pessac, France.
authors.forename: Bernard
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authors.lastname: Veyret
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Luigina
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authors.lastname: Romani
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Ursula
authors.initials: U
authors.lastname: Grohmann
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Paolo
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authors.lastname: Puccetti
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000276:immunology / Q000378:metabolism; D060467:Disease Resistance / Q000187:drug effects / Q000235:genetics* / Q000276:immunology*; D019446:Endotoxemia / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D010766:Phosphorylation; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014366:Tryptophan Oxygenase / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008070:Lipopolysaccharides; D018336:Receptors, Aryl Hydrocarbon; D007737:Kynurenine; D014366:Tryptophan Oxygenase; D019061:src-Family Kinases