Cysteinyl-maresin 3 inhibits IL-13 induced airway hyperresponsiveness through alternative activation of the CysLT1 receptor

• Published in: European journal of pharmacology 2022-11, Vol.934, p.175257-175257, Article 175257
• Main Authors: Säfholm, Jesper, Abma, Willem, Bankova, Lora G., Boyce, Joshua A., Al-Ameri, Mamdoh, Orre, Ann-Charlotte, Wheelock, Craig E., Dahlén, Sven-Erik, Adner, Mikael
• Format: Article
• Language: English
• Subjects: Airway smooth muscle; Hyperresponsiveness; Leukotrienes; Lipid mediators; Maresin conjugates; Medicin och hälsovetenskap; Resolution; Type 2 inflammation
• ISSN: 0014-2999; 1879-0712; 1879-0712
• DOI: 10.1016/j.ejphar.2022.175257

Cysteinyl-maresins, also known as maresin-conjugates in tissue regeneration (MCTRs), are recently discovered lipid mediators proposed to reduce airway inflammation. To investigate the influence of MCTRs on IL-13-induced airway hyperresponsiveness in isolated human and mice airways. Before responsiveness to contractile agonists were assessed in myographs, human small bronchi were cultured for 2 days and mouse tracheas were cultured for 1–4 days. During the culture procedure airways were exposed to interleukin (IL)-13 in the presence or absence of MCTRs. Signalling mechanisms were explored using pharmacologic agonists and antagonists, and genetically modified mice. IL-13 treatment increased contractions to histamine, carbachol and leukotriene D4 (LTD4) in human small bronchi, and to 5-hydroxytryptamine (5-HT) in mouse trachea. In both preparations, co-incubation of the explanted tissues with MCTR3 reduced the IL-13 induced enhancement of contractions. In mouse trachea, this inhibitory effect of MCTR3 was blocked by three different CysLT1 receptor antagonists (montelukast, zafirlukast and pobilukast) during IL-13 exposure. Likewise, MCTR3 failed to reduce the IL-13-induced 5-HT responsiveness in mice deficient of the CysLT1 receptor. However, co-incubation with the classical CysLT1 receptor agonist LTD4 did not alter the IL-13-induced 5-HT hyperreactivity. MCTR3, but not LTD4, decreased the IL-13-induced airway hyperresponsiveness by activation of the CysLT1 receptor. The distinct actions of the two lipid mediators on the CysLT1 receptor suggest an alternative signalling pathway appearing under inflammatory conditions, where this new action of MCTR3 implicates potential to inhibit airway hyperresponsiveness in asthma. [Display omitted] •The pro-resolving lipidmediator MCTR3 reduces hyperresponsiveness induced by IL-13 in human and murine isolated airways.•The effect of MCTR3 is mediated through the CysLT1 receptor but not mimicked by LTD4.•MCTR3 can be of importance to inhibit airway hyperresponsiveness in asthma.