Abstract
EphA2 receptor and its ephrin ligands are involved in virus infection, epithelial permeability, and chemokine secretion. We hypothesized that ephrinA1/ephA2 signaling participates in rhinovirus (RV)-induced antiviral immune response in sinonasal mucosa of patients with chronic rhinosinusitis (CRS). Therefore, we investigated the expression of ephrinA1/ephA2 in normal and inflamed sinonasal mucosa and evaluated whether they regulate chemokine secretion and the production of antiviral immune mediators including interferons (IFNs) in RV-infected human primary sinonasal epithelial cells. For this purpose, the expression and distribution of ephrinA1/ephA2 in sinonasal mucosa were evaluated with RT-qPCR, immunofluorescence, and western blot. Their roles in chemokine secretion and the production of antiviral immune mediators such as type I and III IFNs, and interferon stimulated genes were evaluated by stimulating ephA2 with ephrinA1 and inactivating ephA2 with ephA2 siRNA or inhibitor in cells exposed to RV and poly(I:C). We found that ephrinA1/ephA2 were expressed in normal mucosa and their levels increased in inflamed sinonasal mucosa of CRS patients. RV infection or poly(I:C) treatment induced chemokine secretion which were attenuated by blocking the action of ephA2 with ephA2 siRNA or inhibitor. The production of antiviral immune mediators enhanced by rhinovirus or poly (I:C) is increased by blocking ephA2 compared with that of cells stimulated by either rhinovirus or poly(I:C) alone. In addition, blocking ephA2 attenuated RV replication in cultured cells. Taken together, these results describe a novel role of ephrinA1/ephA2 signaling in antiviral innate immune response in sinonasal epithelium, suggesting their participation in RV-induced development and exacerbations of CRS.
Highlights
Chronic rhinosinusitis (CRS) is a heterogenous mucosal inflammation of the nasal cavity and paranasal sinuses [1]
Our results revealed that ephrin A1 and ephA2 receptor are expressed in normal sinonasal mucosa, and their levels were up-regulated in inflammatory sinonasal mucosa of chronic rhinosinusitis (CRS) patients, regardless of the existence of nasal polyps
Given that the protective effect of ephA2 blocking in RV-induced inflammation, we investigated whether the ephrinA1/ephA2 signaling would affect the existing signaling pathways; PI3K-Akt-NF-kB pathway leading to the activation of host innate immune genes such as chemokines and TBK/IKKε/interferon regulatory factor 3 (IRF3) pathway utilized in the secretion of antiviral immune mediators including IFNs and IFN-stimulated genes (ISGs) [12, 14, 42]
Summary
Chronic rhinosinusitis (CRS) is a heterogenous mucosal inflammation of the nasal cavity and paranasal sinuses [1]. The pathophysiological causes of CRS remain unclear, accumulating evidence suggests that abnormal immune response of sinonasal mucosa to respiratory viral infection can progress to secondary bacterial infection and induce the exacerbation of CRS [2,3,4,5,6]. Rhinovirus (RV) infections are the most common cause of viral upper airway infections [4, 7, 8]. It is unclear why they are self-limiting in the majority of persons, but in others can advance to bacterial sinusitis and enhance CRS exacerbations [2,3,4,5,6]. RV-infected epithelial cells produce chemokines which trigger the chemoattraction of immune cells into infection site to facilitate viral clearance [13, 14]
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