title: Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease.
abstract: Half a century ago, chronic granulomatous disease (CGD) was first described as a disease fatally affecting the ability of children to survive infections. Various milestone discoveries have since been made, from an insufficient ability of patients' leucocytes to kill microbes to the underlying genetic abnormalities. In this inherited disorder, phagocytes lack NADPH oxidase activity and do not generate reactive oxygen species, most notably superoxide anion, causing recurrent bacterial and fungal infections. Patients with CGD also suffer from chronic inflammatory conditions, most prominently granuloma formation in hollow viscera. The precise mechanisms of the increased microbial pathogenicity have been unclear, and more so the reasons for the exaggerated inflammatory response. Here we show that a superoxide-dependent step in tryptophan metabolism along the kynurenine pathway is blocked in CGD mice with lethal pulmonary aspergillosis, leading to unrestrained Vgamma1(+) gammadelta T-cell reactivity, dominant production of interleukin (IL)-17, defective regulatory T-cell activity and acute inflammatory lung injury. Although beneficial effects are induced by IL-17 neutralization or gammadelta T-cell contraction, complete cure and reversal of the hyperinflammatory phenotype are achieved by replacement therapy with a natural kynurenine distal to the blockade in the pathway. Effective therapy, which includes co-administration of recombinant interferon-gamma (IFN-gamma), restores production of downstream immunoactive metabolites and enables the emergence of regulatory Vgamma4(+) gammadelta and Foxp3(+) alphabeta T cells. Therefore, paradoxically, the lack of reactive oxygen species contributes to the hyperinflammatory phenotype associated with NADPH oxidase deficiencies, through a dysfunctional kynurenine pathway of tryptophan catabolism. Yet, this condition can be reverted by reactivating the pathway downstream of the superoxide-dependent step.
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06126 Perugia, Italy. lromani@unipg.it
authors.forename: Luigina
authors.initials: L
authors.lastname: Romani
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
authors.forename: Antonella
authors.initials: A
authors.lastname: De Luca
authors.forename: Claudia
authors.initials: C
authors.lastname: Montagnoli
authors.forename: Carmen
authors.initials: C
authors.lastname: D'Angelo
authors.forename: Teresa
authors.initials: T
authors.lastname: Zelante
authors.forename: Carmine
authors.initials: C
authors.lastname: Vacca
authors.forename: Francesco
authors.initials: F
authors.lastname: Bistoni
authors.forename: Maria C
authors.initials: MC
authors.lastname: Fioretti
authors.forename: Ursula
authors.initials: U
authors.lastname: Grohmann
authors.forename: Brahm H
authors.initials: BH
authors.lastname: Segal
authors.forename: Paolo
authors.initials: P
authors.lastname: Puccetti
mesh_terms: D000818:Animals; D001228:Aspergillosis / Q000150:complications / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D001232:Aspergillus fumigatus / Q000502:physiology; D002908:Chronic Disease; D004195:Disease Models, Animal; D006105:Granulomatous Disease, Chronic / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D007371:Interferon-gamma / Q000276:immunology / Q000627:therapeutic use; D020381:Interleukin-17 / Q000172:deficiency / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism* / Q000627:therapeutic use; D008168:Lung / Q000276:immunology / Q000473:pathology; D008172:Lung Diseases, Fungal / Q000150:complications / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology; D013481:Superoxides / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D014364:Tryptophan / Q000378:metabolism*
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D020381:Interleukin-17; D017382:Reactive Oxygen Species; D016692:Receptors, Antigen, T-Cell, gamma-delta; D013481:Superoxides; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1