Directional Secretory Response of Double Stranded RNA-Induced Thymic Stromal Lymphopoetin (TSLP) and CCL11/Eotaxin-1 in Human Asthmatic Airways

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.

Nasopharyngeal Microbiome in Premature Infants and Stability during Rhinovirus Infection

“…9–12 The VIRAL cohort is a longitudinal study of children admitted to the hospital with suspected viral respiratory infections. W1 was taken during acute RV infection as confirmed by PCR.…”

Immune Responses in Rhinovirus-Induced Asthma Exacerbations

“…These results provide further evidence that RV can induce a type 2 cytokine response that could result in an exaggerated allergic immune response and thereby exacerbations in asthmatic individuals. Less is known concerning the role of TSLP following RV infection, although studies have reported increased levels of TSLP in nasal secretions from asthmatics infected with RV that was not seen in noninfected nonasthmatics [66, 67]. …”

Current and future biomarkers in allergic asthma

“…Clinically defined phenotypes include nonatopic wheezers, viral-induced asthma or multitrigger wheezers that may differentially respond to treatment or may even undergo spontaneous remission and therefore require personalized therapy (10). In fact, rhinovirus infection-induced asthma exacerbations in children were associated with elevated TSLP and CCL-11 (eotaxin-1) levels that can be noninvasively detected in nasal secretions (11). The repeated report of genetic associations of IL-33 and TSLP (12) with asthma risk is particularly interesting as TSLP, IL-25 (IL-17E) and IL-33 (13) are considered to play a role in the early commitment towards Th2 immunity and type 2 innate (ILC2) lymphocytes (14).…”