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Defective tryptophan catabolism underlies inflammation in chronic granulomatous disease of mice

Chronic granulomatous disease (CGD) is an inherited disease, fatally impairing children's ability to survive infections. The cause is a lack of NADPH oxidase activity in the phagocytes that can not generate reactive oxygen species, most notably superoxide anion. Recurring bacterial and fungal infections are the consequences. Patients with CGD also suffer from chronic inflammatory conditions, most prominently granuloma formation in hollow viscera.
In mice with chronic granulomatous disease (CGD), a superoxide-dependent step of the tryptophan metabolism is blocked in the pathway. The mice suffered from lethal pulmonary aspergillosis causing unrestricted reactivity, increased production of , defective regulatory activity and acute inflammatory lung injury. Luigina Romani and her team from the University of Perugia in Italy observed that complete cure and reversal of the hyperinflammatory phenotype succeeded when the distal to the blockade in the pathway was replaced.

An effective therapy required co-administration of recombinant () and was able to restore production of downstream immunoactive metabolites. The therapy also succeeded in releasing regulatory Vγ4+γδ and +αβ .

In absence of reactive oxygen species, the hyperinflammatory phenotype associated with NADPH oxidase deficiencies is stronger, caused by a dysfunctional pathway of tryptophan catabolism. The phenotype can be cured by reactivating the pathway downstream of the superoxide-dependent step.

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