Airway epithelial cells generate pro-inflammatory tenascin-C and small extracellular vesicles in response to TLR3 stimuli and rhinovirus infection

Journal article


Mills, Jake, Schwenzer, Anja, Marsh, Elizabeth, Edwards, Michael, Midwood, Kim, Sabroe, Ian and Parker, Lisa 2019. Airway epithelial cells generate pro-inflammatory tenascin-C and small extracellular vesicles in response to TLR3 stimuli and rhinovirus infection. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2019.01987
AuthorsMills, Jake, Schwenzer, Anja, Marsh, Elizabeth, Edwards, Michael, Midwood, Kim, Sabroe, Ian and Parker, Lisa
Abstract

Viral 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.

KeywordsAsthma exacerbations, human rhinovirus, Tenascin-c, Exosomes, extracellular vesicles, Inflammation, Extracellular Matrix
Year2019
JournalFrontiers in Immunology
PublisherFrontiers
ISSN16643224
Digital Object Identifier (DOI)https://doi.org/10.3389/fimmu.2019.01987
Web address (URL)http://hdl.handle.net/10545/624136
http://creativecommons.org/licenses/by-nc-nd/3.0/us/
hdl:10545/624136
Publication dates21 Aug 2019
Publication process dates
Deposited23 Aug 2019, 14:29
Accepted06 Aug 2019
Rights

Attribution-NonCommercial-NoDerivs 3.0 United States

ContributorsUniversity of Sheffield, University of Oxford, University of Derby and Imperial College London
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