Abstract
Loss of airway epithelial integrity contributes significantly to asthma pathogenesis. Thymic stromal lymphopoietin (TSLP) may have dual immunoregulatory roles. In inflammatory disorders of the bowel, the long isoform of TSLP (lfTSLP) promotes inflammation while the short isoform (sfTSLP) inhibits inflammation. We hypothesize that lfTSLP contributes to house dust mite (HDM)-induced airway epithelial barrier dysfunction and that synthetic sfTSLP can prevent these effects. In vitro, airway epithelial barrier function was assessed by monitoring transepithelial electrical resistance, fluorescent-dextran permeability, and distribution of E-cadherin and β-catenin. In vivo, BALB/c mice were exposed to HDM by nasal inhalation for 5 consecutive days per week to establish an asthma model. sfTSLP and 1α,25-Dihydroxyvitamin D3 (1,25D3) were administered 1 h before HDM exposure. After 8 weeks, animal lung function tests and pathological staining were performed to evaluate asthma progression. We found that HDM and lfTSLP impaired barrier function. Treatment with sfTSLP and 1,25D3 prevented HDM-induced airway epithelial barrier disruption. Moreover, sfTSLP and 1,25D3 treatment ameliorated HDM-induced asthma in mice. Our data emphasize the importance of the different expression patterns and biological properties of sfTSLP and lfTSLP. Moreover, our results indicate that sfTSLP and 1,25D3 may serve as novel therapeutic agents for individualized treatment of asthma.
Highlights
That acts directly on T-cells by controlling Th17 cell differentiation, fosters regulatory T-cell development, and protects against colitis[8]
A previous study demonstrated that the expression of lfTSLP, which is a crucial cytokine for the induction of inflammatory Th2 responses, is highly induced by dsRNA in bronchial epithelial cells[20]
We have shown that the two isoforms of TSLP have different expression patterns and biological properties in HDM-induced asthmatic airway epithelial barrier disruption
Summary
That acts directly on T-cells by controlling Th17 cell differentiation, fosters regulatory T-cell development, and protects against colitis[8]. TSLP can regulate the capacity of tolerogenic DCs to drive the differentiation of natural regulatory T cells both in the intestine and thymus[11,12]. In contrast to these protective effects, TSLP overexpression can be detected in airway epithelia of asthmatic patients and in mice with asthma[13,14,15] and is correlated with the severity of asthma[16]. Another study found that synthetic sfTSLP exerts potent antimicrobial activity and that sfTSLP is the predominant form of TSLP, being the form widely and constitutively expressed in keratinocytes and saliva at steady state, both at the mRNA and protein levels[22]. We found that only lfTSLP contributes to HDM-induced airway epithelial barrier dysfunction and that synthetic sfTSLP prevents this HDM-induced disruption
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