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

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 (HCO3¯) 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 HCO3¯ secretion. TNFα+IL-17 increased expression and function of two apical HCO3¯ transporters, CFTR anion channels and pendrin Cl-/HCO3- exchangers. Both were required for maximal alkalinization. TNFα+IL-17 induced pendrin expression primarily in secretory cells where it was co-expressed with CFTR. Interestingly, significant pendrin expression was not detected in CFTR-rich ionocytes. These results indicate that TNFα+IL-17 stimulate HCO3- secretion via CFTR and pendrin to alkalinize ASL, which may represent an important defense mechanism in inflamed airways.

Paracellular bicarbonate flux across human cystic fibrosis airway epithelia tempers changes in airway surface liquid pH

“…Interestingly, IL‐13 did not alter G p , and in a separate study, one day of IL‐17/TNFα treatment increased ASL pH but did not alter G p (Rehman et al . 2020). These differences highlight the likely contribution of time of treatment and identity of cytokine for responses, as has been previously noted (Coyne et al .…”

Topography-dependent gene expression and function of common cell archetypes in large and small porcine airways

“…We found 2 to 6 ionocytes per 1,000 cells in large airways and none in the small airways. Second, we used protein expression of Barttin (BSND) (Rehman et al, 2020) measured by immunocytochemistry to identify ionocytes in large and small airway tissue. We identified BSND (+) cells in large but not in small airways ( Figure 2B ).…”

Airway Surface Liquid pH Regulation in Airway Epithelium Current Understandings and Gaps in Knowledge

“…Pendrin is expressed preferentially in goblet cells, and at low levels in ciliated epithelial cells, but not in ionocytes [ 120 ]. Its expression at the apical membrane is increased by the pro-inflammatory cytokines IL-4, IL-13, and IL-17A [ 121 , 122 ].…”

“…In primary cultures of differentiated human airway epithelia, and in secretory cells where both proteins were co-expressed, Rehman et al observed that the combination of TNFα+IL-17 increased CFTR and pendrin expression. This was associated with elevated ASL pH stemming from increased HCO 3 − secretion [ 120 ]. Simonin et al [ 58 ] found that inhibition of pendrin by a specific inhibitor decreased ASL pH.…”

“…Recent studies confirmed this selectivity, and showed that the permeabilities of the shunt pathway to Cl − and HCO 3 − are equal, but that their conductances differ due to their different luminal concentrations [ 164 ]. According to the authors’ calculations, the paracellular HCO 3 − flux is secretory under basal conditions (ASL pH < basolateral pH), but it reverses to absorption when ASL pH is >7.0, a condition reached when transcellular HCO 3 − secretion is enhanced by the presence of pro-inflammatory cytokines [ 120 , 164 ].…”