| First Author | Carreño M | Year | 2022 |
| Journal | Sci Adv | Volume | 8 |
| Issue | 26 | Pages | eabm9138 |
| PubMed ID | 35767602 | Mgi Jnum | J:351502 |
| Mgi Id | MGI:7313701 | Doi | 10.1126/sciadv.abm9138 |
| Citation | Carreno M, et al. (2022) Immunomodulatory actions of a kynurenine-derived endogenous electrophile. Sci Adv 8(26):eabm9138 |
| abstractText | 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 kappaB- 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. |
