Letter

Nature 451, 211-215 (10 January 2008) | doi:10.1038/nature06471; Received 19 August 2007; Accepted 13 November 2007

There is a Brief Communication Arising (23 October 2014) associated with this document.

Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease

Luigina Romani1, Francesca Fallarino1, Antonella De Luca1, Claudia Montagnoli1, Carmen D'Angelo1, Teresa Zelante1, Carmine Vacca1, Francesco Bistoni1, Maria C. Fioretti1, Ursula Grohmann1, Brahm H. Segal2 & Paolo Puccetti1

  1. Department of Experimental Medicine, University of Perugia, 06126 Perugia, Italy
  2. Division of Infectious Diseases, Roswell Park Cancer Institute, Buffalo, New York 14263, USA

Correspondence to: Luigina Romani1Paolo Puccetti1 Correspondence and requests for materials should be addressed to L.R. (Email: lromani@unipg.it) or P.P. (Email: plopcc@tin.it).

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 abnormalities1. 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 unclear2, and more so the reasons for the exaggerated inflammatory response3, 4, 5, 6. 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.

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