Carreño Mara, Pires Maria F, Woodcock Steven R, Brzoska Tomasz, Ghosh Samit, Salvatore Sonia R, Chang Fei, Khoo Nicholas K H, Dunn Matthew, Connors Nora, Yuan Shuai, Straub Adam C, Wendell Stacy G, Kato Gregory J, Freeman Bruce A, Ofori-Acquah Solomon F, Sundd Prithu, Schopfer Francisco J, Vitturi Dario A
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA.
Sci Adv. 2022 Jul;8(26):eabm9138. doi: 10.1126/sciadv.abm9138. Epub 2022 Jun 29.
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.
犬尿氨酸代谢的上调通过尚不完全清楚的机制诱导免疫调节反应。我们报告称，细胞和全身犬尿氨酸水平的升高会产生亲电衍生物犬尿氨酸-羧基酮烯（Kyn-CKA），硫醇共轭物和饱和代谢产物的积累证明了这一点。Kyn-CKA诱导NFE2样bZIP转录因子2和芳烃受体调节的基因，并抑制核因子κB和含NLR家族吡咯结构域3的依赖性促炎信号传导。镰状细胞病（SCD）是一种遗传性溶血性疾病，其特征为基础炎症和复发性血管闭塞性危机。转基因SCD小鼠和SCD患者均表现出犬尿氨酸和Kyn-CKA代谢产物水平升高。血浆血红素和犬尿氨酸浓度呈正相关，表明在致病性血管应激期间，SCD中Kyn-CKA的合成上调。给予Kyn-CKA可消除SCD小鼠的肺微血管闭塞，这是肺损伤发展的一个重要因素。这些发现表明，犬尿氨酸合成及其向Kyn-CKA的代谢上调是一种适应性反应，可减轻炎症并保护组织。
