β-Ionone facilitates ex vivo airway smooth muscle relaxation via extraocular opsin-3 light receptor activation

Recent studies have linked deficiencies in β-carotene ingestion and its metabolites with an increased risk and severity of asthma exacerbations. We demonstrate that β-ionone, a β-carotene metabolite, dose-dependently relaxes upper and lower airways in vitro using wire myography of tracheal rings and phase-contrast microscopy of precision-cut lung slices (PCLSs). We demonstrate that β-ionone-induced relaxation is mediated through extraocular opsin-3 (OPN3) receptor activation via pharmacological competitive inhibition with chromophore 9-<i>cis</i> retinal and through the decreased relaxation demonstrated in Opn3-null PCLSs. We implicate a mechanistic pathway suggestive of G_αs activation that is in agreement with our previous findings. Finally, we confirmed OPN3 expression in airway smooth muscle cells by immunofluorescence and mRNA expression. Our findings implicate β-ionone as a potential therapeutic agent for conditions characterized by bronchoconstriction, such as asthma and COPD. Moreover, this study underscores the significance of dietary intake, particularly of β-carotene-rich foods, in maintaining respiratory health.<b>NEW & NOTEWORTHY</b> This research investigates β-ionone's potential as a therapeutic agent for bronchoconstriction. It sheds light on the mechanism of action of β-ionone's activation of extraocular opsin-3 receptors, offering insights into dietary influences on respiratory health. Notably, β-ionone induces dose-dependent relaxation in both upper and lower airways, with attenuated relaxation in Opn3-knockout models confirming receptor selectivity. This study presents a novel approach to addressing respiratory ailments and underscores the significance of dietary components in managing airway pathology.