Immunomodulatory actions of a kynurenine-derived endogenous electrophile
Year: 2022
Type: article
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.
Source: Science Advances
Authors: Mara Carreño, Maria F. Pires, Steven R. Woodcock, Tomasz Brzoska, Samit Ghosh, Sonia R. Salvatore, Fei Chang, Nicholas K. H. Khoo, Matthew Dunn, Nora Connors, Shuai Yuan, Adam C. Straub, Stacy G. Wendell, Gregory J. Kato, Bruce A. Freeman, Solomon F. Ofori-Acquah, Prithu Sundd, Francisco J. Schopfer, Dario A. Vitturi
Institutions: University of Pittsburgh, CSL (United States), University of Ghana
Language: English
Subfield: Biological Psychiatry
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,500
Funders: American Heart Association, Hemophilia Center of Western Pennsylvania, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: Redox-Derived Pulmonary Anti-Inflammatory Mediators, G1281970666, Novel role of smooth muscle B5 reductase in Sickle Cell Disease, Targeting Uric Acid as a Therapeutic for NASH, Iron Redox Regulation: Basic Mechanisms, Translational Implications and Strategies to Treat Cardiovascular Disease, Predominant protective role in hepatic steatosis and obesity by fish oil-derived furans, Nitric Oxide Regulation of Vascular Oxidant Injury, Therapeutic Targeting of Vascular Subphenotypes of Lung Disease, Vascular Smooth Muscle and Blood Pressure Regulation By Cyb5R3², SickleGenAfrica:Sickle Cell Disease Genomics Network of Africa, Anti-inflammatory actions of a novel hemin-induced electrophile in Sickle Cell Disease, G7519571385, Pittsburgh Center for Kidney Research, Protection against sickle cell disease nephropathy by nitrated fatty acids, Mechanisms of platelet exosome-mediated acute chest syndrome in sickle cell disease, Biological actions of endogenous Kynurenine-derived electrophiles, Molecular and Cellular Pathogenesis of Kidney Disease in Sickle Cell Disorders, Pittsburgh Liver Research Center, Pulmonary arteriole occlusion by platelet-neutrophil micro-emboli in Acute Chest Syndrome, Formation and metabolism of nitrated fatty acids, Basic and Translational Studies in Redox Regulation of Cardiovascular Physiology and Disease, Renal endothelium and the development of chronic kidney disease in sickle cell disorders
OpenAlex ID: W4283725452