Abstract
The function of chemokine receptors on structural cells is only partially known. We previously reported the expression of a functional CCR3 receptor on airway epithelial cells (EC). We speculated that CCR3 might drive wound repair and expression of inflammatory genes in epithelium. The human airway EC lines BEAS-2B, 16-HBE, and primary bronchial EC were used to test the effect of in vitro challenge with the CCR3 ligands CCL11/eotaxin, CCL24/eotaxin-2, or CCL26/eotaxin-3 on 1) wound repair, using an established wound model; 2) cell proliferation and chemotaxis, using specific fluorometric assays; and 3) gene expression, using pathway-specific arrays for inflammatory and profibrotic cytokines, chemokines, and chemokine receptor genes. Agonist specificity was tested by cell pretreatment with an AstraZeneca CCR3 antagonist (10(-8) - 10(-6) M). CCL24 challenge significantly accelerated epithelial wound closure, with similar effects exerted by CCL11 and CCL26. This effect was time dependent, submaximal at 1 nM, and comparable in potency to epidermal growth factor. CCL24 induced a concentration-dependent increase in EC proliferation and chemotaxis, with significant effects observed at 10 nM. The AstraZeneca compound selectively inhibited these CCL24-mediated responses. CCL11 induced the up-regulation of several profibrogenic molecules such as fibroblast growth factor 1 and 5 and of several CC and CXC chemokines. Epithelial immunostaining for CCR3 was stronger in bronchial biopsies of asthmatics displaying marked inflammatory changes than in nondiseased samples. Epithelial CCR3 participates in key functions for wound repair, amplifies the expression of profibrogenic and chemokine transcripts, and appears up-regulated in inflamed asthmatic airways.
Highlights
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Our present study indicates the novel involvement of the chemokine network in the epithelial wound repair process in the airways, as we report that a specific CCR3 ligand, CCL24, is able to accelerate epithelial cells (EC) wounding in vitro by promoting the chemotaxis as well as the proliferation of airway EC, a response that can be blocked by a selective CCR3 antagonist
We compared the effect of an equimolar concentration (10 nM) of the CCR3 ligands CCL11 and CCL26
Summary
EC, epithelial cell; AZ XX, AstraZeneca CCR3 antagonist; BMP, bone morphogenic protein; EGF, epidermal growth factor; FGF, fibroblast growth factor; HVEM-L, herpes virus entry mediator-ligand; PBEC, primary bronchial EC; TNFSF, TNF (ligand) superfamily; RT, room temperature; MFI, mean fluorescence intensity. The wound healing process is a complex biological response involving multiple events, including profound changes in EC phenotype, activation of chemotaxis of cells from the epithelial basal layer, followed by cell proliferation and differentiation, as well as by changes in gene expression All these processes are controlled by receptor-mediated signals generated by growth factors such as the tyrosine kinase receptor ligand, epidermal growth factor (EGF) [10]. Immunohistochemical analysis of biopsy samples from asthmatic airways show more intense CCR3 staining of airway epithelium, compared with control samples These data reveal a novel chemokine-driven pathway that targets EC functions, such as proliferation and chemotaxis, which are key components of the wound repair process and might be altered in several diseases in which EC play a pathogenetic role. Our data strongly suggest the existence of an epithelialderived, CCR3-mediated network aimed at amplifying chemokinemediated responses
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