Abstract
The role of antimicrobial peptide LL-37 in asthma exacerbation is unclear. Microbial infection, which is the most common inducer of asthma exacerbation, is accompanied by elevated LL-37. The present study found that co-culture of eosinophils and bronchial epithelial cell line BEAS-2B significantly enhanced intercellular adhesion molecule-1 on both cells and CD18 expression on eosinophils upon LL-37 stimulation. IL-6, CXCL8 and CCL4 were substantially released in co-culture in the presence of LL-37. LL-37 triggered the activation of eosinophils interacting with BEAS-2B cells in a P2X purinoceptor 7/epidermal growth factor receptor-dependent manner. Eosinophils and BEAS-2B cells differentially contribute to the expression of cytokines/chemokines in co-culture, while soluble mediators were sufficient to mediate the intercellular interactions. Intracellular p38-mitogen-activated protein kinase, extracellular signal-regulated kinase and NF-κB signaling pathways were essential for LL-37-mediated activation of eosinophils and BEAS-2B cells. By using the ovalbumin-induced asthmatic model, intranasal administration of mCRAMP (mouse ortholog of LL-37) in combination with ovalbumin during the allergen challenge stage significantly enhanced airway hyperresponsiveness and airway inflammation in sensitized mice, thereby implicating a deteriorating role of LL-37 in allergic asthma. This study provides evidence of LL-37 in triggering asthma exacerbation via the activation of eosinophils interacting with bronchial epithelial cells in inflammatory airway.
Highlights
Asthma is an increasingly prevalent allergic disease that is characterized by T helper type 2 (Th2) lymphocyte dominated airway inflammation, hypersensitivity and remodeling[9]
No variations in CD18 were observed on BEAS-2B cells, significantly higher levels of surface CD18 expression were detected on co-cultured eosinophils with LL-37 (10 μg/ml) stimulation (Fig. 1A,C)
The co-culture of eosinophils and BEAS-2B cells released larger amount of IL-6, CXCL8 and CCL4 in the presence of LL-37 (Fig. 2A–C). These findings collectively indicate that intercellular interactions between eosinophils and bronchial epithelial cells are necessary for the optimal LL-37-mediated cell activation
Summary
Asthma is an increasingly prevalent allergic disease that is characterized by T helper type 2 (Th2) lymphocyte dominated airway inflammation, hypersensitivity and remodeling[9]. LL-37 has been reported to induce the release of the proinflammatory, spasmogenic cysteinyl leukotrienes (CysLTs) from human eosinophils, implicating an immunopathological role of LL-37 in asthma by mediating the expression of CysLTs13. Asthma exacerbation is an aggravated disease stage in asthmatic patients that is triggered by diverse factors, including viral/bacterial infections and allergen/irritant exposures[14]. Previous studies have established a close link between respiratory viral/bacterial infections and asthma exacerbation[14], it remains unknown whether the expression of LL-37 that associates with the innate response to airway infections might be involved in the exacerbation of the disease by activating eosinophils. The aim of the present study was to investigate the underlying mechanisms between LL-37 and asthma exacerbation both in vitro by using co-culture system of eosinophils and bronchial epithelial cells and in vivo by using ovalbumin (OVA)-induced mouse model of allergic airway inflammation
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