Kynurenine metabolites predict survival in pulmonary arterial hypertension: A role for IL-6/IL-6Rα

Zongye Cai, Siyu Tian, Theo Klein, Ly Tu, Laurie W. Geenen, Thomas Koudstaal, Annemien E. van den Bosch, Yolanda B. de Rijke, Irwin K.M. Reiss, Eric Boersma, Claude van der Ley, Martijn Van Faassen, Ido Kema, Dirk J. Duncker, Karin A. Boomars, Karin Tran-Lundmark, Christophe Guignabert, Daphne Merkus*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Activation of the kynurenine pathway (KP) has been reported in patients with pulmonary arterial hypertension (PAH) undergoing PAH therapy. We aimed to determine KP-metabolism in treatment-naïve PAH patients, investigate its prognostic values, evaluate the effect of PAH therapy on KP-metabolites and identify cytokines responsible for altered KP-metabolism. KP-metabolite levels were determined in plasma from PAH patients (median follow-up 42 months) and in rats with monocrotaline- and Sugen/hypoxia-induced PH. Blood sampling of PAH patients was performed at the time of diagnosis, six months and one year after PAH therapy. KP activation with lower tryptophan, higher kynurenine (Kyn), 3-hydroxykynurenine (3-HK), quinolinic acid (QA), kynurenic acid (KA), and anthranilic acid was observed in treatment-naïve PAH patients compared with controls. A similar KP-metabolite profile was observed in monocrotaline, but not Sugen/hypoxia-induced PAH. Human lung primary cells (microvascular endothelial cells, pulmonary artery smooth muscle cells, and fibroblasts) were exposed to different cytokines in vitro. Following exposure to interleukin-6 (IL-6)/IL-6 receptor α (IL-6Rα) complex, all cell types exhibit a similar KP-metabolite profile as observed in PAH patients. PAH therapy partially normalized this profile in survivors after one year. Increased KP-metabolites correlated with higher pulmonary vascular resistance, shorter six-minute walking distance, and worse functional class. High levels of Kyn, 3-HK, QA, and KA measured at the latest time-point were associated with worse long-term survival. KP-metabolism was activated in treatment-naïve PAH patients, likely mediated through IL-6/IL-6Rα signaling. KP-metabolites predict response to PAH therapy and survival of PAH patients.

Original languageEnglish
Article number12326
JournalScientific Reports
Volume12
Issue number1
DOIs
Publication statusPublished - 19 Jul 2022

Bibliographical note

Funding Information:
This work was supported by the China Scholarship Council (201606230252 to ZC & 201708130077 to ST), the China Postdoctoral Science Foundation (2020M680079 and 2021T140598 to ZC), the National Natural Science Foundation of China (82100060 to ZC), the Netherlands CardioVascular Research Initiative: an initiative with support of the Dutch Heart Foundation (CVON2014-11, RECONNECT, to DM and DJD), and German Center for Cardiovascular Research (DZHK81Z0600207 to DM). Instrumentation support was received from AB Sciex, ltd. for LC–MS/MS analyses performed in this study.

Publisher Copyright: © 2022, The Author(s).

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