Targeting TSLP With shRNA Alleviates Airway Inflammation and Decreases Epithelial CCL17 in a Murine Model of Asthma

Abstract

Airway epithelium defends the invasion from microorganisms and regulates immune responses in allergic asthma. Thymic stromal lymphopoietin (TSLP) from inflamed epithelium promotes maturation of dendritic cells (DCs) to prime Th2 responses via CCL17, which induces chemotaxis of CD4+ T cells to mediate inflammation. However, few studies have investigated the regulation of epithelial CCL17. In this study, we used shRNA against TSLP to clarify the role of TSLP in the airway inflammation and whether TSLP affects the airway inflammation via epithelial CCL17. Specific shTSLP was delivered by lentivirus and selected by the knockdown efficiency. Allergic mice were intratracheally pretreated with the lentivirus and followed by intranasal ovalbumin (OVA) challenges. The sera antibody levels, airway inflammation, airway hyper-responsiveness (AHR), cytokine levels in bronchoalveolar lavage fluids, and CCL17 expressions in lungs were determined. In vivo, TSLP attenuation reduced the AHR, decreased the airway inflammation, inhibited the maturations of DCs, and suppressed the migration of T cells. Furthermore, the expression of CCL17 was particularly decreased in bronchial epithelium. In vitro, CCL17 induction was regulated by TSLP. In conclusion, TSLP might coordinate airway inflammation partially via CCL17-mediated responses and this study provides the vital utility of TSLP to develop the therapeutic approach in allergic airway inflammation.

ITGB4is essential for containing HDM-induced airway inflammation and airway hyperresponsiveness

“…As an epithelium‐derived cytokine, TSLP represents a master switch at the interface between environmental allergens and pulmonary allergic immunologic responses . TSLP was verified to be a sufficient and necessary factor for the initiation of allergic airway inflammation by contacting lung DCs . Thus, we further detected TSLP expression in lung after HDM stress.…”

“…33 TSLP was verified to be a sufficient and necessary factor for the initiation of allergic airway inflammation by contacting lung DCs. 34 Thus, we further detected TSLP expression in lung after HDM stress. TSLP mRNA expression in lung was upregulated significantly in the HDM stressed ITGB4 −/− mice compared with control mice (Fig.…”

<p>GM-CSF: A Promising Target in Inflammation and Autoimmunity</p>

“…Interestingly, it has been reported that alveolar DC-derived CCL17 is critical for airway inflammation 169 , 170 and CCL17 airway expression correlates with asthmatic disease severity. 171 , 172 In our view these data warrant a detailed study examining the role of the GM-CSF/CCL17 axis in asthma, with CCL17 being a potential target for treating allergic disease and/or a biomarker for patient selection.…”

Role of epithelial chemokines in the pathogenesis of airway inflammation in asthma (Review)

“…The specific enhanced expression of TSLP in airway epithelial cells results in initial CD4 + T lymphocyte proliferation and Th2 cell differentiation (38). Conversely, targeting TSLP with short hairpin RNA or antibodies, alleviates airway inflammation and decreases epithelial CCL17 in a murine model of asthma (51,52).…”