IL13 activates autophagy to regulate secretion in airway epithelial cells

Abstract

Cytokine modulation of autophagy is increasingly recognized in disease pathogenesis, and current concepts suggest that type 1 cytokines activate autophagy, whereas type 2 cytokines are inhibitory. However, this paradigm derives primarily from studies of immune cells and is poorly characterized in tissue cells, including sentinel epithelial cells that regulate the immune response. In particular, the type 2 cytokine IL13 (interleukin 13) drives the formation of airway goblet cells that secrete excess mucus as a characteristic feature of airway disease, but whether this process is influenced by autophagy was undefined. Here we use a mouse model of airway disease in which IL33 (interleukin 33) stimulation leads to IL13-dependent formation of airway goblet cells as tracked by levels of mucin MUC5AC (mucin 5AC, oligomeric mucus/gel forming), and we show that these cells manifest a block in mucus secretion in autophagy gene Atg16l1-deficient mice compared to wild-type control mice. Similarly, primary-culture human tracheal epithelial cells treated with IL13 to stimulate mucus formation also exhibit a block in MUC5AC secretion in cells depleted of autophagy gene ATG5 (autophagy-related 5) or ATG14 (autophagyrelated 14) compared to nondepleted control cells. Our findings indicate that autophagy is essential for airway mucus secretion in a type 2, IL13-dependent immune disease process and thereby provide a novel therapeutic strategy for attenuating airway obstruction in hypersecretory inflammatory diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis lung disease. Taken together, these observations suggest that the regulation of autophagy by Th2 cytokines is cell-context dependent.

Autophagy mediates epithelial cytoprotection in eosinophilic oesophagitis

“…IL-4 and IL-13 suppress autophagy in epithelial and immune cells responding to starvation and Mycobacterium tuberculosis infection, respectively. 32 33 The current study, along with a recent report demonstrating that IL-13 activates autophagy in airway epithelial cells to promote mucus secretion, 34 indicates that regulation of autophagy by Th2 cytokines may be cell type dependent and/or context dependent. As primary oesophageal keratinocytes from normal and active EoE mucosa display similar autophagy level at baseline and in response to TNF-α in vitro (see online supplementary figure S6), we propose that autophagy activation in EoE patients results from exposure to the inflammatory milieu rather than from any intrinsic alteration in oesophageal keratinocytes.…”

Physicochemical properties of mucus and their impact on transmucosal drug delivery

“…Investigating the role of mucins both in health and disease has been of great interest, and from substantial progress in the past two decades. Specific mucins decreased production, secretion, and expression are potential novel strategies being evaluated for the treatment of pathologic mucus in airway inflammatory diseases (Bae et al, 2014; Dickinson et al, 2016; Fahy and Dickey, 2010; Ha and Rogers, 2016; Lee et al, 2016). …”

TP53-dependent autophagy links the ATR-CHEK1 axis activation to proinflammatory VEGFA production in human bronchial epithelial cells exposed to fine particulate matter (PM2.5)

“…[10][11][12] Among these processes, respiratory pathologies such as asthma, chronic obstructive pulmonary disease, respiratory tract infection and pulmonary fibrosis, are closely correlated with autophagy, which has been extensively studied and discussed. [13][14][15][16][17] The findings indicate that excessive autophagy in chronic lung diseases not only is essential for airway mucus hyper-secretion and airway remodeling, 14,15 but also functions mechanistically to impair the host antiviral defense against respiratory viral infections and to promote airway epithelial fibrosis. Therefore, manipulating autophagic pathways and their regulatory components might lead to the development of therapeutics for lung diseases.…”

“…To examine the signal transduction pathways leading to VEGFA induction, we first addressed the possible involvement of autophagy, a well-known metabolic process closely related to lung pathogenesis, [13][14][15][16][17] in mediating VEGFA upregulation under PM2.5 exposure. Because an increase in the MAP1LC3B/LC3B (microtubule-associated protein light chain 3 b)-II:LC3B-I ratio, the induction of BECN1/BECLIN 1 (Beclin 1) expression and a decrease in SQSTM1/p62 (sequestosome 1) levels are hallmarks of autophagosome accumulation and autophagic degradation, 23 we first analyzed the levels of these specific autophagic key proteins using a western blot assay.…”