Pendrin stimulates a chloride absorption pathway to increase CFTR‐mediated chloride secretion from Cystic Fibrosis airway epithelia

Abstract

Cystic Fibrosis (CF), an inherited multi‐system disease, is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) that disrupt its ability to secrete anions from epithelia. Recovery of functional anion secretion may be curative for CF, so different components of the ion transport machinery have become attractive therapeutic targets. Several members of the SLC26 ion transporter family have been linked to epithelial ion flux, some through putative functional interactions with CFTR. Using a small‐scale qPCR screen, we confirmed that the anion transporter SLC26A4 (pendrin) is downregulated in CF. Upregulation of pendrin using interleukins IL‐4 or IL‐13 increased Cl− secretion through CFTR in human bronchial epithelial cell (HBEC) derived epithelia differentiated in vitro and measured in the Ussing Chamber. Inhibition or knockdown of pendrin prevented this increased secretion. Increased CFTR activity was not driven by increases in CFTR protein or upstream regulatory pathway components. When basolateral Cl− absorption through NKCC1 was inhibited, a pendrin‐dependent Cl− absorption pathway allowing CFTR to continue secreting Cl− from the epithelium was revealed. Although CFTR is often considered the bottleneck in the transepithelial Cl− transport pathway, these studies indicate that basolateral Cl− permeability becomes limiting as CFTR activity increases. Therefore, an increase of epithelial Cl− absorption via pendrin might have additional therapeutic benefit in combination with CFTR modulators.

Measuring cystic fibrosis drug responses in organoids derived from 2D differentiated nasal epithelia

“…Organoid swelling was partly attenuated with the Na(+)-K(+)-Cl(−) cotransporter (NKCC1) inhibitor bumetanide, demonstrating Cl − dependence of forskolin-induced organoid fluid secretion ( Fig S2E and F ). Lack of complete inhibition may be explained by reabsorption and recycling of luminal-secreted Cl − or an ion channel–independent mechanism underlying fluid secretion caused by mechanical forces ( Bajko et al, 2020 ; Buddington et al, 2021 ). Moreover, chemical CFTR inhibitors significantly reduced FIS in HC NAOs ( Fig S2G and H ), indicating CFTR dependence.…”

Chloride/Multiple Anion Exchanger SLC26A Family: Systemic Roles of SLC26A4 in Various Organs

“…IL-4 and IL-13 activate SLC26A4 and CFTR in CF airway epithelial cells [87]. In addition, IL-4/IL-13-induced CFTR activation is attenuated by treatment with SLC26A4 inhibitor niflumic acid [87].…”

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

“…Indeed upregulation of pendrin transcription has been shown in chronic rhinosinusitis and in rodent models of inflammatory lung diseases [ 125 , 126 , 127 ]. More recently, Bajko et al [ 128 ] showed that stimulation with interleukins IL-4, IL-13, or IL-17a increased pendrin levels in human bronchial epithelial cells from CF patients (CF HBECs) and non-CF donors (HBECs) [ 121 , 129 ]. Indeed, modulation of pendrin expression/activity by inflammation may represent a protective mechanism for re-alkalinization of ASL and epithelium defense during disease.…”