Immunomodulatory actions of a kynurenine-derived endogenous electrophile.

Abstract

The inflammatory upregulation of kynurenine metabolism induces immunomodulatory responses via incompletely understood mechanisms. We report that increases in cellular and systemic kynurenine levels yield the electrophilic derivative kynurenine-carboxyketoalkene (Kyn-CKA), as evidenced by the accumulation of thiol-conjugates and saturated metabolites. Under physiological conditions, Kyn-CKA induces Nrf2-regulated genes and inhibits NF-{kappa}B and NLRP3-dependent pro-inflammatory signaling. Sickle Cell Disease (SCD) is a hereditary hemolytic condition characterized by basal inflammation and recurrent vaso-occlusive crises. Both a transgenic SCD murine model and SCD patients exhibit increased kynurenine synthesis and elevated Kyn-CKA metabolite levels. Plasma hemin and kynurenine concentrations are positively correlated, indicating that Kyn-CKA synthesis in SCD is upregulated during pathogenic vascular stress. Remarkably, exogenous administration of Kyn-CKA abrogated pulmonary microvasculature occlusion in SCD mice, an important factor in the development of lung injury. These findings demonstrate that the upregulation of kynurenine synthesis and its metabolism to Kyn-CKA is an adaptive response that attenuates inflammation and protects tissues. One-Sentence SummaryKyn-CKA is a kynurenine-derived signaling mediator that transduces its immunomodulatory protective actions and attenuates vaso-occlusion in sickle cell disease.