Human rhinovirus induce specific bronchial smooth muscle migration toward bronchial epithelium in severe asthma through the CXCL10/CXCR3 axis

Abstract

Rhinovirus (RV) infection of the bronchial epithelium (BE) is the main trigger of severe asthma exacerbations. Interestingly, severe asthmatic also exhibit an increase of bronchial smooth muscle (BSM) mass. A decreased distance between BE and BSM is correlated to the severity of the disease and suggest a role of BSM cells migration toward epithelium in BSM remodelling of severe asthmatic patients. We investigate chemotaxis effect of RV-infected BE on BSM cells using primary BE and BSM cells obtained from non-asthmatic and severe asthmatic patients. BSM migration was assessed by live video microscopy in response to RV-infected BE supernatant. Our study unveiled the implication of CXCL10/CXCR3 axis which has been analysed using ELISA, immunostaining, western blot, flow cytometry and real-time calcium fluorescence. We demonstrate a specific migration of severe asthmatic BSM cells towards RV-infected BE. Transcriptomic analysis show an increase of CXCL-10 in RV-infected supernatant which was confirmed both in vitro and ex vivo. On the BSM side, the blocking of CXCL10 receptor (i.e CXCR3), abolished severe asthmatic BSM cells migration. CXCR3-A and B isoforms have antagonist effects on cell migration (activation and inhibition respectively). We found an increased expression and activation of CXCR3-B pathway in non-asthmatic BSM cells in response to CXCL10. However, CXCR3-A expression and calcium dependant activation are increased in severe asthmatic BSM cells. This CXCR3 isoform-dependant mechanism unveils a new role of rhinovirus-infection on BSM remodelling which could be a new therapeutic target against this unmet need in severe asthma.