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. 2019 Feb 14;10:51. doi: 10.3389/fphar.2019.00051

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Copyright © 2019 Miner, Labitzke, Liu, Wang, Henckels, Gaida, Elliott, Chen, Liu, Leith, Trueblood, Hensley, Xia, Homann, Bennett, Fiorino, Whoriskey, Yu, Escobar, Wong, Born, Budelsky, Comeau, Smith, Phillips, Johnston, McGivern, Weikl, Powers, Kunzelmann, Mohn, Hochheimer and Sullivan.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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TMEM16A is expressed in cultured human airway smooth muscle and bronchial epithelial cells, quickly upregulated in mature human bronchial epithelial air-liquid interface (ALI) cultures after IL-4 or IL-13 treatment and overexpressed in the lung of asthmatic cynomolgus monkeys on the apical surface of goblet cells and in submucosal glands. TMEM16A (ANO1) expression in cultured human bronchial epithelial cells (HBE, submerged) and human airway smooth muscle cells from normal, asthmatic or COPD donors (A) was determined from an RNAseq dataset described earlier (Aisenberg et al., 2016). TMEM16A expression was higher in bronchial epithelial cells compared to airway smooth muscle cells. The results for ASM cells (normal or diseased) are from 3 separate donors each, while the results for HBE cells are the average response from 8 normal, 5 asthma and 3 COPD donors. The Th2 cytokine, IL-13, dramatically increased TMEM16A (ANO1) gene expression in mature bronchial epithelial ALI cultures reaching a maximum after 1 day (B, left panel), while elevated expression of the MUC5AC gene (B, right panel) occurred more slowly from day 1 through day 5 or 7. The RNAseq data shown are from ALI cultures from two normal (green; C1,C4) and three COPD (purple; C2, C3, C5) donors, untreated (Ctrl, open circles) or treated with IL-13 (closed circles). The Th2 cytokines, IL-4 and IL-13, also upregulated TMEM16A protein expression in human bronchial epithelial air-liquid interface cultures (C). Fully differentiated human bronchial epithelial ALI cultures were untreated (C, left panel) or treated for 48 h with IL-4 (C, middle panel) or IL-13 (C, right panel), fixed and stained with a rabbit anti-TMEM16A monoclonal antibody from Abcam (Ab64085). Increased TMEM16A staining (brown) was detected in basal cells located near the membrane insert and basolateral surface (left side of ALI culture) and on goblet cells located at the apical surface (right side) of IL-4 or IL-13 treated ALI cultures. Elevated TMEM16A protein expression was also detected in the bronchiolar epithelium and submucosal glands of cynomolgus monkeys with allergic asthma (D). Cynomolgus monkeys repeatedly challenged with Ascaris suum were compared to naïve non-allergic monkeys for TMEM16A expression using the polyclonal antibody Ab53212 (Abcam). Increased TMEM16A staining (brown) was observed on the apical surface of the bronchial epithelium and in submucosal glands of monkey with allergic asthma (D, right panel; animal #384630) compared to a naïve non-allergic monkey (D, left panel; animal #384606). Lung specimens from a separate asthmatic cynomolgus monkey (#384750) were collected 24 h post A. suum challenge. Immunohistochemical staining with the anti-TMEM16A antibody indicates TMEM16A is expressed selectively on the apical surface of goblet cells within the bronchial epithelium (E).