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

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Abstract
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 ([ ]) and acid (H+) to control ASL pH (pHASL). Neutrophil-predominant inflammation is a hallmark of several airway diseases, and TNFα and IL-17 are key drivers. However, how these cytokines perturb pHASL regulation is uncertain. In primary cultures of differentiated human airway epithelia, TNFα decreased and IL-17 did not change pHASL. However, the combination (TNFα+IL-17) markedly increased pHASL by increasing [ ] secretion. TNFα+IL-17 increased expression and function of two apical [ ] transporters, CFTR anion channels and pendrin Cl−/[ ] exchangers. Both were required for maximal alkalinization. TNFα+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 TNFα+IL-17 stimulate [ ] secretion via CFTR and pendrin to alkalinize ASL, which may represent an important defense mechanism in inflamed airways.
Funding Information
  • HHS | National Institutes of Health (HL051670, HL091842, HL007638)
  • Cystic Fibrosis Foundation (Research Development Program, RDP Pilot)
  • Howard Hughes Medical Institute
  • Gilead Sciences (Research Program in Cystic Fibrosis)

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