Abstract

The respiratory tract possesses a highly regulated innate defence system which includes cilia-mediated mucociliary clearance (MCC). Efficient MCC relies on appropriate hydration of airway surfaces, which is controlled by a blend of transepithelial sodium and liquid absorption, and anion and liquid secretion The latter is primarily mediated by the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. Succinate is derived from parasites, microorganisms and inflammatory cells, and its concentration increases in the airway surface liquid (ASL) during infections, activating the G-protein coupled succinate receptor (SUCNR1), which acts as a succinate sensor. Since MCC is tightly regulated by second messengers we tested the hypothesis that succinate signalling was linked to CFTR activity. We observed that SUCNR1 activation stimulated anion secretion, increased mucus transport, and induced tracheal constriction in mouse airways. In the CftrΔF508/ΔF508 mouse, increased mucus transport and tracheal constriction were observed, while succinate-induced electrogenic anion secretion remained unaffected. Stimulation of normal human bronchial epithelial cells (HBECs) with succinate activated CFTR-dependent anion secretion and increased ASL height. Moreover, when HBECs derived from ΔF508-CF individuals lacked succinate-induced anion secretion, unless incubated with elexacaftor-tezacaftor-ivacaftor (ETI), which restored succinate-induced anion secretion, confirming the tight relationship between SUCNR1 signalling and CFTR function. We have identified a novel mechanism for regulating CFTR/MCC activation which is defective in CF airways. We propose that succinate acts as a danger molecule that alerts the airways to the presence of pathogens leading to a flushing out of the airways.