Abstract
Chronic allergic asthma is characterized by Th2-typed inflammation, and contributes to airway remodeling and the deterioration of lung function. However, the initiating factor that links airway inflammation to remodeling is unknown. Thymic stromal lymphopoietin (TSLP), an epithelium-derived cytokine, can strongly activate lung dendritic cells (DCs) through the TSLP-TSLPR and OX40L-OX40 signaling pathways to promote Th2 differentiation. To determine whether TSLP is the underlying trigger of airway remodeling in chronic allergen-induced asthma, we induced allergic airway inflammation in mice by intranasal administration of house dust mite (HDM) extracts for up to 5 consecutive weeks. We showed that repeated respiratory exposure to HDM caused significant airway eosinophilic inflammation, peribronchial collagen deposition, goblet cell hyperplasia, and airway hyperreactivity (AHR) to methacholine. These effects were accompanied with a salient Th2 response that was characterized by the upregulation of Th2-typed cytokines, such as IL-4 and IL-13, as well as the transcription factor GATA-3. Moreover, the levels of TSLP and transforming growth factor beta 1 (TGF-β1) were also increased in the airway. We further demonstrated, using the chronic HDM-induced asthma model, that the inhibition of Th2 responses via neutralization of TSLP with an anti-TSLP mAb reversed airway inflammation, prevented structural alterations, and decreased AHR to methacholine and TGF-β1 level. These results suggest that TSLP plays a pivotal role in the initiation and persistence of airway inflammation and remodeling in the context of chronic allergic asthma.
Highlights
Allergic asthma is a common respiratory disease caused by chronic exposure to environmental aeroantigens like house dust mite (HDM), with the hallmark of airway chronic inflammation and structural alterations [1,2,3]
Increased Thymic stromal lymphopoietin (TSLP) mRNA and protein levels in the lung were dramatically inhibited by pretreatment with anti-TSLP mAb, compared with the levels that were observed in the IgG isotype-treated control mice, even though the former group was continuously exposed to HDM from the 4th week to the 5th week (Figure 2A and 2B)
We showed that exposure to HDM for 5 consecutive weeks induced a robust airway inflammation, characterized by the influx of inflammatory cells, including eosinophils and lymphocytes (Figure 3H)
Summary
Allergic asthma is a common respiratory disease caused by chronic exposure to environmental aeroantigens like house dust mite (HDM), with the hallmark of airway chronic inflammation and structural alterations [1,2,3]. This chronic inflammation driven by Th2 responses is considered to be the underlying cause of damage to the airway epithelium. In mice that overexpress Tbet, the Th1/Th2 balance was shifted to Th1, and structural remodeling of airway walls was prevented following allergen exposure [10]. The initiating factor that links airway inflammation to remodeling in chronic asthma remains unclear
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