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.
Highlights
The pH of airway surface liquid (ASL), the thin layer of fluid that covers the airway epithelium, is a key factor that determines airway host defense [70, 85]
In striking contrast to the individual cytokines, the combination of TNF␣ϩIL-17 markedly increased pH of ASL (pHASL). These results suggest that TNF␣ regulates pHASL differently than IL-17 and that TNF␣ and IL-17 signaling pathways interact to produce an unexpectedly large increase in pHASL
CFTR knockdown reduced pHASL in both untreated and TNF␣ϩIL-17-treated epithelia (Fig. 3, B and C). These results indicate that CFTR contributed to the TNF␣ϩIL-17-induced increase in pHASL
Summary
The pH of airway surface liquid (ASL), the thin layer of fluid that covers the airway epithelium, is a key factor that determines airway host defense [70, 85]. Two of the main defense mechanisms in human airways are mucociliary clearance and antimicrobial factor-mediated bacterial killing. In proximal airways under normal, healthy conditions, acid secretion occurs primarily through Hϩ/Kϩ ATPase (ATP12A) [20, 77], other pathways may be involved, including monocarboxylate transporters (MCT) [29], Hϩ channels (HVCN1), Naϩ/Hϩ exchangers (NHE3), and other Hϩ-pumps (V-type ATPase) [27]. Base (HCO3Ϫ) ily through CFTR anion channels (50, secretion occurs primar69, 81), Ca2ϩactivated anion channels (TMEM16A), the SLC26A9 anion transporter, and the ClϪ/HCO3Ϫ countertransporter pendrin (SLC26A4) have been reported to play a role to a varying extent [8, 13, 28, 41, 44, 49, 64]
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