The Expression of ephrinA1/ephA2 Receptor Increases in Chronic Rhinosinusitis and ephrinA1/ephA2 Signaling Affects Rhinovirus-Induced Innate Immunity in Human Sinonasal Epithelial Cells

• Published in: Frontiers in immunology Vol. 12; p. 793517
• Main Authors: Lee, Sang Hag, Kang, Sung Hoon, Han, Mun Soo, Kwak, Ji Won, Kim, Hyeon Geun, Lee, Tae Hoon, Lee, Da Bin, Kim, Tae Hoon
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 16.12.2021
• Subjects: Case-Control Studies; Cells, Cultured; Chronic Disease; chronic rhinosinusitis with nasal polyps; chronic rhinosinusitis without nasal polyps; Common Cold - immunology; Common Cold - metabolism; Common Cold - virology; Cytokines - metabolism; Ephrin-A1 - genetics; Ephrin-A1 - metabolism; Ephrin-A2 - genetics; Ephrin-A2 - metabolism; ephrinA1/ephA2 signaling; Epithelial Cells - drug effects; Epithelial Cells - immunology; Epithelial Cells - metabolism; Epithelial Cells - virology; Host-Pathogen Interactions; Humans; Immunity, Innate; Immunology; interferon stimulated genes; Nasal Mucosa - drug effects; Nasal Mucosa - immunology; Nasal Mucosa - metabolism; Nasal Mucosa - virology; Poly I-C - pharmacology; Receptor, EphA2 - genetics; Receptor, EphA2 - metabolism; Rhinitis - immunology; Rhinitis - metabolism; Rhinovirus - growth & development; Rhinovirus - immunology; Rhinovirus - pathogenicity; Signal Transduction; Sinusitis - immunology; Sinusitis - metabolism; type I interferon; type III interferon; Virus Replication; type I interferon; type III interferon; innate immune response; chronic rhinosinusitis with nasal polyps; ephrinA1/ephA2 signaling; chronic rhinosinusitis without nasal polyps; rhinovirus; interferon stimulated genes
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.793517

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.