title: Th17/Treg imbalance in murine cystic fibrosis is linked to indoleamine 2,3-dioxygenase deficiency but corrected by kynurenines.
abstract: BACKGROUND
  Mutations in the cystic fibrosis (CF) transmembrane conductance regulator affect the innate epithelial immune function of the lung, resulting in exaggerated and ineffective airway inflammation that fails to eradicate pathogenic fungi. The appreciation of whether such fungi are primarily responsible for or a consequence of ineffective airway inflammation is important for future therapeutics development.
  
  
  OBJECTIVE
  To characterize the impact of the tryptophan/kynurenine pathway on pathogenic airway inflammation preventing effective fungal clearance in CF.
  
  
  METHODS
  We studied the expression of indoleamine 2,3-dioxygenase (IDO), the first enzyme in the kynurenine pathway of tryptophan degradation, in human and murine CF, the impact of IDO on lung inflammation and immunity in murine CF, and the potential role of tryptophan catabolism in pathogenesis and therapy of fungus-associated lung inflammation.
  
  
  RESULTS
  IDO was defective in murine and human CF. Genetic and transcriptional regulatory mechanisms contributed to dysfunctional IDO activity that, in turn, correlated with imbalanced Th17/Treg-cell responses to Aspergillus fumigatus in murine CF. Treatments enhancing IDO function or preventing pathogenic Th17-cell activation restored protective immunity to the fungus and improved lung inflammation in murine CF.
  
  
  CONCLUSIONS
  This study provides a link between tryptophan catabolism and lung immune homeostasis in murine CF, representing a proof-of-concept that targeting pathogenic inflammation via IDO-mimetic drugs may benefit patients with CF.
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, Perugia, Italy.
authors.forename: Rossana G
authors.initials: RG
authors.lastname: Iannitti
authors.forename: Agostinho
authors.initials: A
authors.lastname: Carvalho
authors.forename: Cristina
authors.initials: C
authors.lastname: Cunha
authors.forename: Antonella
authors.initials: A
authors.lastname: De Luca
authors.forename: Gloria
authors.initials: G
authors.lastname: Giovannini
authors.forename: Andrea
authors.initials: A
authors.lastname: Casagrande
authors.forename: Teresa
authors.initials: T
authors.lastname: Zelante
authors.forename: Carmine
authors.initials: C
authors.lastname: Vacca
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
authors.forename: Paolo
authors.initials: P
authors.lastname: Puccetti
authors.forename: Cristina
authors.initials: C
authors.lastname: Massi-Benedetti
authors.forename: Gloria
authors.initials: G
authors.lastname: Defilippi
authors.forename: Maria
authors.initials: M
authors.lastname: Russo
authors.forename: Luigi
authors.initials: L
authors.lastname: Porcaro
authors.forename: Carla
authors.initials: C
authors.lastname: Colombo
authors.forename: Luigi
authors.initials: L
authors.lastname: Ratclif
authors.forename: Fernando M
authors.initials: FM
authors.lastname: De Benedictis
authors.forename: Luigina
authors.initials: L
authors.lastname: Romani
mesh_terms: D000818:Animals; D003550:Cystic Fibrosis / Q000201:enzymology* / Q000382:microbiology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000172:deficiency* / Q000378:metabolism*; D007737:Kynurenine / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D058504:Th17 Cells / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine