Attenuation of Dupuytren’s fibrosis via targeting of the STAT-1 modulated IL-13RA1 response

Akbar, M., Garcia-Melchor, E., Chilaka, S., Little, K. J., Sood, S., Reilly, J. H., Liew, F. Y., McInnes, I. B. and Millar, N. L. (2020) Attenuation of Dupuytren’s fibrosis via targeting of the STAT-1 modulated IL-13RA1 response. Science Advances, 6(28), eaaz8272. (doi: 10.1126/sciadv.aaz8272)

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Abstract

Fibrotic disorders represent common complex disease pathologies that are therapeutically challenging. Inflammation is associated with numerous fibrotic pathogeneses; however, its role in the multifaceted mechanisms of fibrosis remains unclear. IL-13 is implicated in aberrant responses involved in fibrotic disease, and we aimed to understand its role in the inflammatory processes of a common fibrotic disorder, Dupuytren’s disease. We demonstrated T-cells produced IFN-g, which induced IL-13 secretion from mast cells and up-regulated IL-13Ra1 on fibroblasts, rendering them more reactive to IL-13. Consequently, diseased myofibroblasts demonstrated enhanced fibroproliferative effects upon IL-13 stimulation. We established IFN-g and IL-13 responses involved STAT dependent pathways, and STAT targeting (tofacitinib) could inhibit IL-13 production from mast cells, IL-13Ra1 up-regulation in fibroblasts and fibroproliferative effects of IL-13 on diseased myofibroblasts. Accordingly, utilizing Dupuytren’s as an accessible human model of fibrosis, we propose targeting STAT pathways may offer previously unidentified therapeutic approaches in the management of fibrotic disease.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McInnes, Professor Iain and Liew, Prof Foo and Sood, Dr Shatakshi and Garcia Melchor, Dr Emma and Akbar, Mr Moeed and Reilly, Mr James and Chilaka, Dr Sabarinadh and Millar, Professor Neal
Authors: Akbar, M., Garcia-Melchor, E., Chilaka, S., Little, K. J., Sood, S., Reilly, J. H., Liew, F. Y., McInnes, I. B., and Millar, N. L.
College/School:UNSPECIFIED
Journal Name:Science Advances
Publisher:American Association for the Advancement of Science
ISSN:2375-2548
ISSN (Online):2375-2548
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Science Advances 6(28):eaaz8272
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
301515Damage mechanisms in tendon diseaseNeal MillarMedical Research Council (MRC)MR/R020515/1III - Immunology