Abstract
Airway mucus obstruction is the main cause of morbidity in cystic fibrosis, a disease caused by mutations in the CFTR Cl- channel. Activation of non-CFTR Cl- channels such as TMEM16A can likely compensate for defective CFTR. However, TMEM16A was recently described as a key driver in mucus production/secretion. Here, we have examined whether indeed there is a causal relationship between TMEM16A and MUC5AC production, the main component of respiratory mucus. Our data show that TMEM16A and MUC5AC are inversely correlated during differentiation of human airway cells. Furthermore, we show for the first time that the IL-4-induced TMEM16A up-regulation is proliferation-dependent, which is supported by the correlation found between TMEM16A and Ki-67 proliferation marker during wound healing. Consistently, the notch signaling activator DLL4 increases MUC5AC levels without inducing changes neither in TMEM16A nor in Ki-67 expression. Moreover, TMEM16A inhibition decreased airway surface liquid height. Altogether, our findings demonstrate that up-regulation of TMEM16A and MUC5AC is only circumstantial under cell proliferation, but with no causal relationship between them. Thus, although essential for airway hydration, TMEM16A is not required for MUC5AC production.
Highlights
Mucus clearance or mucociliary transport (MCT) consists the coordinated integration of ion transport, water flow, mucin secretion, cilia action, and coughing, resulting in the continuous flow of fluid and mucus on airway surfaces (Button et al, 2008)
Specific inflammatory/immune response mediators lead to mucus hyperproduction in each of these chronic airway diseases through activation of mucin gene expression and airway remodeling, including goblet cell metaplasia or hyperplasia (GCM/H: reviewed in (Rose & Voynow, 2006))
An association between the expression of transmembrane protein 16 A (TMEM16A) and MUC5AC was previously reported by several authors (Huang et al, 2012; Scudieri et al, 2012; Lin et al, 2015; Qin et al, 2016; Kang et al, 2017; Kondo et al, 2017; Benedetto et al, 2019)
Summary
Mucus clearance or mucociliary transport (MCT) consists the coordinated integration of ion transport, water flow, mucin secretion, cilia action, and coughing, resulting in the continuous flow of fluid and mucus on airway surfaces (Button et al, 2008). The main mucins present in human airway mucus are MUC5AC and MUC5B, which are mostly secreted from goblet cells at the surface airway epithelium and by submucosal glands, respectively (Buisine et al, 1999; Bonser & Erle, 2017). Specific inflammatory/immune response mediators lead to mucus hyperproduction in each of these chronic airway diseases through activation of mucin gene expression and airway remodeling, including goblet cell metaplasia or hyperplasia (GCM/H: reviewed in (Rose & Voynow, 2006)). Mucin overproduction and GCM/H, linked, are not synonymous and may result from different signaling and gene regulatory pathways (Rose & Voynow, 2006)
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