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Allergenic proteases cleave the chemokine CX3CL1 directly from the surface of airway epithelium and augment the effect of Rhinovirus

Allergenic proteases cleave the chemokine CX3CL1 directly from the surface of airway epithelium and augment the effect of Rhinovirus
Allergenic proteases cleave the chemokine CX3CL1 directly from the surface of airway epithelium and augment the effect of Rhinovirus
CX3CL1 has been implicated in allergen-induced airway CD4+ T lymphocyte recruitment in asthma. Since epidemiological evidence supports a viral infection-allergen synergy in asthma exacerbations, we postulated that rhinovirus (RV) infection in the presence of allergen augments epithelial CX3CL1 release. Fully differentiated primary bronchial epithelial cultures were pre-treated apically with house dust mite extract (HDM) and infected with RV16. CX3CL1 was measured by ELISA and western blotting, and shedding mechanisms assessed using inhibitors, PAR2 agonist, and recombinant CX3CL1-expressing HEK293 cells. Basolateral CX3CL1 release was unaffected by HDM but stimulated by RV16; inhibition by fluticasone or GM6001 implicated NF-κB and ADAM sheddases. Conversely, apical CX3CL1 shedding was stimulated by HDM, augmented by RV16. Although fluticasone or GM6001 reduced RV16+HDM-induced apical CX3CL1 release, heat-inactivation or cysteine protease inhibition completely blocked CX3CL1 shedding. HDM effect was via enzymatic cleavage of CX3CL1, not PAR2 activation, yielding a product mitogenic for smooth muscle cells. Extracts of Alternaria fungus caused similar CX3CL1 shedding. We have identified a novel mechanism whereby allergenic proteases cleave CX3CL1 from the apical epithelial surface to yield an active product. RV16 infection augmented HDM-induced CX3CL1 shedding – this may contribute to synergy between allergen exposure and RV infection in triggering asthma exacerbations and airway remodelling.
airway epithelium, CX3CL1, Fractalkine, aeroallergens, rhinovirus, protease, Asthma
1933-0219
404-414
Loxham, Matthew
8ef02171-9040-4c1d-8452-2ca34c56facb
Smart, David
3468eafa-5280-40a1-9fda-1bdc07dd914f
Bedke, Nicole
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Smithers, Natalie
63ead01b-6515-4f82-a963-884f572af872
Filippi, Irene
46f16884-ad61-4502-a706-7565e07da0b2
Blume, Cornelia
aa391c64-8718-4238-906b-d6bb1551a07b
Swindle, Emily
fe393c7a-a513-4de4-b02e-27369bd7e84f
Tariq, Kamran
4de9ca91-e58a-49d7-970b-1b1cada17cf7
Howarth, Peter
ff19c8c4-86b0-4a88-8f76-b3d87f142a21
Holgate, Stephen
2e7c17a9-6796-436e-8772-1fe6d2ac5edc
Davies, Donna
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Loxham, Matthew
8ef02171-9040-4c1d-8452-2ca34c56facb
Smart, David
3468eafa-5280-40a1-9fda-1bdc07dd914f
Bedke, Nicole
981dbd61-1912-4231-b6d5-42520c38178d
Smithers, Natalie
63ead01b-6515-4f82-a963-884f572af872
Filippi, Irene
46f16884-ad61-4502-a706-7565e07da0b2
Blume, Cornelia
aa391c64-8718-4238-906b-d6bb1551a07b
Swindle, Emily
fe393c7a-a513-4de4-b02e-27369bd7e84f
Tariq, Kamran
4de9ca91-e58a-49d7-970b-1b1cada17cf7
Howarth, Peter
ff19c8c4-86b0-4a88-8f76-b3d87f142a21
Holgate, Stephen
2e7c17a9-6796-436e-8772-1fe6d2ac5edc
Davies, Donna
7de8fdc7-3640-4e3a-aa91-d0e03f990c38

Loxham, Matthew, Smart, David, Bedke, Nicole, Smithers, Natalie, Filippi, Irene, Blume, Cornelia, Swindle, Emily, Tariq, Kamran, Howarth, Peter, Holgate, Stephen and Davies, Donna (2017) Allergenic proteases cleave the chemokine CX3CL1 directly from the surface of airway epithelium and augment the effect of Rhinovirus. Mucosal Immunology, 11, 404-414. (doi:10.1038/mi.2017.63).

Record type: Article

Abstract

CX3CL1 has been implicated in allergen-induced airway CD4+ T lymphocyte recruitment in asthma. Since epidemiological evidence supports a viral infection-allergen synergy in asthma exacerbations, we postulated that rhinovirus (RV) infection in the presence of allergen augments epithelial CX3CL1 release. Fully differentiated primary bronchial epithelial cultures were pre-treated apically with house dust mite extract (HDM) and infected with RV16. CX3CL1 was measured by ELISA and western blotting, and shedding mechanisms assessed using inhibitors, PAR2 agonist, and recombinant CX3CL1-expressing HEK293 cells. Basolateral CX3CL1 release was unaffected by HDM but stimulated by RV16; inhibition by fluticasone or GM6001 implicated NF-κB and ADAM sheddases. Conversely, apical CX3CL1 shedding was stimulated by HDM, augmented by RV16. Although fluticasone or GM6001 reduced RV16+HDM-induced apical CX3CL1 release, heat-inactivation or cysteine protease inhibition completely blocked CX3CL1 shedding. HDM effect was via enzymatic cleavage of CX3CL1, not PAR2 activation, yielding a product mitogenic for smooth muscle cells. Extracts of Alternaria fungus caused similar CX3CL1 shedding. We have identified a novel mechanism whereby allergenic proteases cleave CX3CL1 from the apical epithelial surface to yield an active product. RV16 infection augmented HDM-induced CX3CL1 shedding – this may contribute to synergy between allergen exposure and RV infection in triggering asthma exacerbations and airway remodelling.

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Fractalkine Manuscript MucImm R2 FINAL CLEAN NOTRACK FIGS - Accepted Manuscript
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More information

Accepted/In Press date: 29 May 2017
e-pub ahead of print date: 5 July 2017
Keywords: airway epithelium, CX3CL1, Fractalkine, aeroallergens, rhinovirus, protease, Asthma
Organisations: Southampton Marine & Maritime Institute, Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 410981
URI: https://eprints.soton.ac.uk/id/eprint/410981
ISSN: 1933-0219
PURE UUID: 3274f14d-3fb1-4b0d-ac7f-4faea064d633
ORCID for Matthew Loxham: ORCID iD orcid.org/0000-0001-6459-538X
ORCID for Cornelia Blume: ORCID iD orcid.org/0000-0001-6133-7318
ORCID for Emily Swindle: ORCID iD orcid.org/0000-0003-3644-7747
ORCID for Donna Davies: ORCID iD orcid.org/0000-0002-5117-2991

Catalogue record

Date deposited: 12 Jun 2017 16:31
Last modified: 10 Dec 2019 06:00

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