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Immunomodulatory actions of a kynurenine-derived endogenous electrophile.
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.
Afiliación
  • Carreño M; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
  • Pires MF; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
  • Woodcock SR; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
  • Brzoska T; Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA.
  • Ghosh S; Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
  • Salvatore SR; Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA.
  • Chang F; Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
  • Khoo NKH; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
  • Dunn M; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
  • Connors N; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
  • Yuan S; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, USA.
  • Straub AC; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
  • Wendell SG; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
  • Kato GJ; Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA.
  • Freeman BA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
  • Ofori-Acquah SF; Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA.
  • Sundd P; Center for Microvascular Research, University of Pittsburgh, Pittsburgh, PA, USA.
  • Schopfer FJ; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
  • Vitturi DA; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, USA.
Sci Adv ; 8(26): eabm9138, 2022 Jul.
Article en En | MEDLINE | ID: mdl-35767602
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.

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Sci Adv Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Sci Adv Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos