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: 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, Paolo Puccetti
• Journal: Nature (Nature) Vol. 511 Issue 7508 Pg. 184-90 (Jul 10 2014) ISSN: 1476-4687 [Electronic] England
• PMID: 24930766 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• IDO1 protein, mouse
• Indoleamine-Pyrrole 2,3,-Dioxygenase
• Lipopolysaccharides
• Receptors, Aryl Hydrocarbon
• Kynurenine
• Tryptophan Oxygenase
• src-Family Kinases

Topics

• Animals
• Bacterial Infections (immunology, metabolism)
• Disease Resistance (drug effects, genetics, immunology)
• Endotoxemia (genetics, immunology, metabolism)
• Enzyme Activation (drug effects)
• Gene Expression Regulation (drug effects)
• Indoleamine-Pyrrole 2,3,-Dioxygenase (metabolism)
• Inflammation (enzymology, genetics, metabolism)
• Kynurenine (metabolism)
• Lipopolysaccharides (pharmacology)
• Mice
• Phosphorylation
• Receptors, Aryl Hydrocarbon (genetics, metabolism)
• Signal Transduction
• Tryptophan Oxygenase (metabolism)
• src-Family Kinases (metabolism)