Abstract
BackgroundThymic stromal lymphoproetin (TSLP) is a cytokine secreted by the airway epithelium in response to respiratory viruses and it is known to promote allergic Th2 responses in asthma. This study investigated whether virally-induced secretion of TSLP is directional in nature (apical vs. basolateral) and/or if there are TSLP-mediated effects occurring at both sides of the bronchial epithelial barrier in the asthmatic state.MethodsPrimary human bronchial epithelial cells (HBEC) from control (n = 3) and asthmatic (n = 3) donors were differentiated into polarized respiratory tract epithelium under air-liquid interface (ALI) conditions and treated apically with dsRNA (viral surrogate) or TSLP. Sub-epithelial effects of TSLP were examined in human airway smooth muscle cells (HASMC) from normal (n = 3) and asthmatic (n = 3) donors. Clinical experiments examined nasal airway secretions obtained from asthmatic children during naturally occurring rhinovirus-induced exacerbations (n = 20) vs. non-asthmatic uninfected controls (n = 20). Protein levels of TSLP, CCL11/eotaxin-1, CCL17/TARC, CCL22/MDC, TNF-α and CXCL8 were determined with a multiplex magnetic bead assay.ResultsOur data demonstrate that: 1) Asthmatic HBEC exhibit an exaggerated apical, but not basal, secretion of TSLP after dsRNA exposure; 2) TSLP exposure induces unidirectional (apical) secretion of CCL11/eotaxin-1 in asthmatic HBEC and enhanced CCL11/eotaxin-1 secretion in asthmatic HASMC; 3) Rhinovirus-induced asthma exacerbations in children are associated with in vivo airway secretion of TSLP and CCL11/eotaxin-1.ConclusionsThere are virally-induced TSLP-driven secretory immune responses at both sides of the bronchial epithelial barrier characterized by enhanced CCL11/eotaxin-1 secretion in asthmatic airways. These results suggest a new model of TSLP-mediated eosinophilic responses in the asthmatic airway during viral-induced exacerbations.
Highlights
The conducting airway epithelium in humans is organized as a pseudostratified columnar structure with a functional polarity and well-defined apical and basolateral compartments [1, 2]
We studied the specific effect of apical thymic stromal lymphopoetin (TSLP) in differentiated human bronchial epithelial cells (HBEC) and the potential sub-epithelial immunomodulatory action of TSLP in human airway smooth muscle cells (HASMC) obtained from control and asthmatic subjects
Prior studies have reported that the toll-like receptor 3 (TLR-3) agonist, dsRNA induces TSLP secretion in submerged HBEC [8, 23]
Summary
The conducting airway epithelium in humans is organized as a pseudostratified columnar structure with a functional polarity and well-defined apical and basolateral compartments [1, 2]. There is evidence that double stranded (ds) RNA, a viral surrogate that activates innate pattern recognition receptors in human bronchial epithelial cells (HBEC) [7], promotes sub-epithelial Th2 immune responses through the secretion of the Th2 master cytokine thymic stromal lymphopoetin (TSLP) [8]. This study investigated whether virally-induced secretion of TSLP is directional in nature (apical vs basolateral) and/or if there are TSLP-mediated effects occurring at both sides of the bronchial epithelial barrier in the asthmatic state. Methods: Primary human bronchial epithelial cells (HBEC) from control (n53) and asthmatic (n53) donors were differentiated into polarized respiratory tract epithelium under air-liquid interface (ALI) conditions and treated apically with dsRNA (viral surrogate) or TSLP. Results: Our data demonstrate that: 1) Asthmatic HBEC exhibit an exaggerated apical, but not basal, secretion of TSLP after dsRNA exposure; 2) TSLP exposure
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