TNF and IL-17 alkalinize airway surface liquid through CFTR and pendrin

The pH of airway surface liquid (ASL) is a key factor that determines respiratory host defense; ASL acidification impairs and alkalinization enhances key defense mechanisms. Under healthy conditions, airway epithelia secrete base (HCO_3-) and acid (H+) to control ASL pH (pH_ASL). Neutrophil-predominant inflammation is a hallmark of several airway diseases, and TNF and IL-17 are key drivers. However, how these cytokines perturb pH_ASL regulation is uncertain. In primary cultures of differentiated human airway epithelia, TNF decreased and IL-17 did not change pH_ASL. However, the combination (TNF+IL-17) markedly increased pH_ASL by increasing HCO_3- secretion. TNF+IL-17 increased expression and function of two apical HCO_3- transporters, CFTR anion channels and pendrin Cl-/HCO_3- exchangers. Both were required for maximal alkalinization. TNF+IL-17 induced pendrin expression primarily in secretory cells where it was coexpressed with CFTR. Interestingly, significant pendrin expression was not detected in CFTR-rich ionocytes. These results indicate that TNF+IL-17 stimulate HCO_3- secretion via CFTR and pendrin to alkalinize ASL, which may represent an important defense mechanism in inflamed airways.