Biomaterial Database

Immunomodulatory actions of a kynurenine-derived endogenous electrophile. 2022

Mara Carreño, and Maria F Pires, and Steven R Woodcock, and Tomasz Brzoska, and Samit Ghosh, and Sonia R Salvatore, and Fei Chang, and Nicholas K H Khoo, and Matthew Dunn, and Nora Connors, and Shuai Yuan, and Adam C Straub, and Stacy G Wendell, and Gregory J Kato, and Bruce A Freeman, and Solomon F Ofori-Acquah, and Prithu Sundd, and Francisco J Schopfer, and Dario A Vitturi

Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.

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.