Succinate Chemosensing Induces Cystic Fibrosis Transmembrane Conductance Regulator-dependent Airway Clearance that Is Impaired in Cystic Fibrosis

The respiratory tract possesses a highly regulated innate defense system that 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, as well as anion and liquid secretion. The latter is mediated primarily 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 during infections, activating the G protein-coupled succinate receptor (SUCNR1), which acts as a succinate sensor. Because MCC is tightly regulated by second messengers, we tested the hypothesis that succinate signaling 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 <i>Cftr</i>^{ΔF508/ΔF508} mouse, increased mucus transport and tracheal constriction were not observed, whereas succinate-induced electrogenic anion secretion remained unaffected. Stimulation of normal human bronchial epithelial cells with succinate activated CFTR-dependent anion secretion and increased airway surface liquid height. Moreover, human bronchial epithelial cells derived from ΔF508-CF individuals that lacked succinate-induced anion secretion, unless incubated with elexacaftor-tezacaftor-ivacaftor, which restored succinate-induced anion secretion, confirmed the tight relationship between SUCNR1 signaling and CFTR function. We have identified a novel mechanism for regulating CFTR/MCC activation that is defective in cystic fibrosis 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.