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dc.contributor.authorMills, Jake
dc.contributor.authorSchwenzer, Anja
dc.contributor.authorMarsh, Elizabeth
dc.contributor.authorEdwards, Michael
dc.contributor.authorMidwood, Kim
dc.contributor.authorSabroe, Ian
dc.contributor.authorParker, Lisa
dc.date.accessioned2019-08-23T14:29:53Z
dc.date.available2019-08-23T14:29:53Z
dc.date.issued2019-08-21
dc.identifier.citationMills, J.T., Schwenzer, A., Marsh, E.K., Edwards, M.R., Sabroe, I., Midwood, K.S. and Parker, L.C., (2019) 'Airway Epithelial Cells Generate Pro-Inflammatory Tenascin-C and Small Extracellular Vesicles in Response to TLR3 Stimuli and Rhinovirus Infection'. Frontiers in Immunology, 10, pp. 1-27. DOI: 10.3389/fimmu.2019.01987.en_US
dc.identifier.doi10.3389/fimmu.2019.01987
dc.identifier.urihttp://hdl.handle.net/10545/624136
dc.description.abstractViral infections are a common cause of asthma exacerbations, with human rhinoviruses (RV) the most common trigger. RV signals through a number of different receptors, including toll-like receptor (TLR)3. Tenascin-C (TN-C) is an immunomodulatory extracellular matrix protein present in high quantities in the airway of people with asthma, and expression is also upregulated in nasal lavage fluid in response to RV infection. Respiratory viral infection has been demonstrated to induce the release of small extracellular vesicles (sEV) such as exosomes, whilst exosomal cargo can also be modified in the bronchoalveolar lavage fluid of people with asthma. These sEVs may potentiate airway inflammation and regulate the immune response to infection. This study characterises the relationship between RV infection of bronchial epithelial cells and the release of TN-C, and the release of sEVs following stimulation with the TLR3 agonist and synthetic viral mimic, poly(I:C), as well as the function of the released protein / vesicles. The BEAS-2B airway epithelial cell line and primary human bronchial epithelial cells (PBECs) from asthmatic and non-asthmatic donors were infected with RV or treated with poly(I:C). TN-C expression, release and localisation to sEVs was quantified. TN-C expression was also assessed following intra-nasal challenge of C57BL/6 mice with poly(I:C). BEAS-2B cells and macrophages were subsequently challenged with TN-C, or with sEVs generated from BEAS-2B cells pre-treated with siRNA targeted to TN-C or control. The results revealed that poly(I:C) stimulation induced TN-C release in vivo, whilst both poly(I:C) stimulation and RV infection promoted release in vitro, with elevated TN-C release from PBECs obtained from people with asthma. Poly(I:C) also induced the release of TN-C-rich sEVs from BEAS-2B cells. TN-C, and sEVs from poly(I:C) challenged cells, induced cytokine synthesis in macrophages and BEAS-2B cells, whilst sEVs from control cells did not. Moreover, sEVs with approximately 75% reduced TN-C content did not alter the capacity of sEVs to induce inflammation. This study identifies two novel components of the inflammatory pathway that regulates the immune response following RV infection and TLR3 stimulation, highlighting TN-C release and pro-inflammatory sEVs in the airway as relevant to the biology of virally induced exacerbations of asthma.en_US
dc.description.sponsorshipThis work was supported by Asthma UK (AUK-PHD-2013-243), which was a four-year funded Asthma UK PhD Studentship.en_US
dc.language.isoenen_US
dc.publisherFrontiersen_US
dc.relation.urlhttps://www.frontiersin.org/articles/10.3389/fimmu.2019.01987/abstracten_US
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/us/*
dc.subjectAsthma exacerbations, human rhinovirus, Tenascin-c, Exosomes, extracellular vesicles, Inflammation, Extracellular Matrixen_US
dc.titleAirway epithelial cells generate pro-inflammatory tenascin-C and small extracellular vesicles in response to TLR3 stimuli and rhinovirus infectionen_US
dc.typeArticleen_US
dc.identifier.eissn16643224
dc.contributor.departmentUniversity of Sheffielden_US
dc.contributor.departmentUniversity of Oxforden_US
dc.contributor.departmentUniversity of Derbyen_US
dc.contributor.departmentImperial College Londonen_US
dc.identifier.journalFrontiers in Immunologyen_US
dcterms.dateAccepted2019-08-06
refterms.dateFOA2019-08-23T14:29:53Z
dc.author.detail785801en_US


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