Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease


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 Vγ1+ γδ 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 γδ 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-γ (IFN-γ), restores production of downstream immunoactive metabolites and enables the emergence of regulatory Vγ4+ γδ and Foxp3+ αβ 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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Figure 1: Invasive pulmonary aspergillosis in the p47 phox mouse knockout model of CGD.
Figure 2: Defective IDO-dependent conversion of tryptophan to l -kynurenine in p47 phox knockout mice.
Figure 3: In A. fumigatus infection, disparate subsets of γδ T cells accumulate in the lungs of CGD (knockout) mice and wild-type controls treated with placebo or 1-MT.
Figure 4: Combined treatment with l -kynurenine and IFN-γ protects CGD mice from invasive pulmonary aspergillosis.


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This work was supported by Specific Targeted Research Project ‘MANASP’ (L.R.), and funding from the Juvenile Diabetes Research Foundation (P.P.) We thank P. Mosci for maintaining the mutant strains of mice and performing histopathology; and G. Andrielli for digital art and image editing.

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Correspondence to Luigina Romani or Paolo Puccetti.

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Supplementary Information

The file contains Supplementary Notes with additional references; Supplementary Figures S1-S5 with Legends, including a schematic Figure S2a that summarizes the main rationale of the study and Supplementary Tables S1-S5. (PDF 2453 kb)

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Romani, L., Fallarino, F., De Luca, A. et al. Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease. Nature 451, 211–215 (2008).

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