Tryptophan/kynurenine metabolism in human leukocytes is independent of superoxide and is fully maintained in chronic granulomatous disease.
ABSTRACT In chronic granulomatous disease (CGD), defective phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity causes reduced superoxide anion (O(2)(·)) radical production leading to frequent infections as well as granulomas and impaired wound healing indicative of excessive inflammation. Based on recent mouse studies, the lack of O(2)(·)-dependent interferon γ (IFNγ)-induced synthesis of kynurenine (kyn), an anti-inflammatory tryptophan metabolite produced by indolamine 2,3 deoxygenase (IDO), was proposed as a cause of hyperinflammation in CGD and this pathway has been considered for clinical intervention. Here, we show that IFNγ induces normal levels of kynurenine in cultures of O(2)(·)-deficient monocytes, dendritic cells, and polymorphonuclear leukocytes from gp91(PHOX)- or p47(PHOX)-deficient human CGD donors. Kynurenine accumulation was dose- and time-dependent as was that of a downstream metabolite, anthranilic acid. Furthermore, urinary and serum levels of kynurenine and a variety of other tryptophan metabolites were elevated rather than suppressed in CGD donors. Although we did not specifically evaluate kyn metabolism in local tissue or inflamed sites in humans, our data demonstrates that O(2)(·) anion is dispensable for the rate-limiting step in tryptophan degradation, and CGD patients do not appear to have either hematopoietic cell or systemic deficits in the production of the anti-inflammatory kynurenine molecule.
Article: Romani & Puccetti reply.Nature 10/2014; 514(7523):E18. DOI:10.1038/nature13845 · 42.35 Impact Factor
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ABSTRACT: Chronic granulomatous disease (CGD) is an inherited disorder of phagocyte function, caused by a genetic defect in NADPH oxidase (NOX2), leading to an impaired ability of leukocytes to produce superoxide ( )1; CGD subjects are susceptible to chronic infections and hyper-inflammation, although the mechanisms remain unclear. Romani et al.2 reported an aberrant inflammatory response to pulmonary aspergillosis as well as sterile Aspergillus fumigatus to be mediated by a defective tryptophan catabolism to kynurenine caused by lack of in CGD mice. Kynurenine is formed by indoleamine 2,3-dioxygenase-1 (IDO1) in a reaction originally reported to depend on (ref. 3). Here we show that NOX2 deficiency does not attenuate IDO1-mediated tryptophan catabolism in human phagocytes and CGD mice with granulomas arising from an inflammatory response to Aspergillus.Nature 10/2014; 514(7523-7523):E16-E17. DOI:10.1038/nature13844 · 42.35 Impact Factor