Immunomodulatory actions of a kynurenine-derived endogenous electrophile
Mara Carreño, Maria F. Pires, Steven R. Woodcock, Tomasz Brzóska, Samit Ghosh, Sonia R. Salvatore, Fei Chang, Nicholas K.H. Khoo, Matthew D. Dunn, Nora Connors, Shuai Yuan, Adam C. Straub, Stacy G. Wendell, Gregory J. Kato, Bruce Α. Freeman, Solomon F. Ofori‐Acquah, Prithu Sundd, Francisco J. Schöpfer, Darío A. Vitturi
Abstract
The up-regulation 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. Kyn-CKA induces NFE2 like bZIP transcription factor 2- and aryl hydrocarbon receptor-regulated genes and inhibits nuclear factor κB- and NLR family pyrin domain containing 3-dependent proinflammatory signaling. Sickle cell disease (SCD) is a hereditary hemolytic condition characterized by basal inflammation and recurrent vaso-occlusive crises. Both transgenic SCD mice and patients with SCD exhibit increased kynurenine and Kyn-CKA metabolite levels. Plasma hemin and kynurenine concentrations are positively correlated, indicating that Kyn-CKA synthesis in SCD is up-regulated during pathogenic vascular stress. Administration of Kyn-CKA abrogated pulmonary microvasculature occlusion in SCD mice, an important factor in lung injury development. These findings demonstrate that the up-regulation of kynurenine synthesis and its metabolism to Kyn-CKA is an adaptive response that attenuates inflammation and protects tissues.