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Lookup NU author(s): Dr Julie Worrell, Dr Jack LeslieORCiD, Dr Graham Smith, Marco Zaki, Dr Hannah Paish, Amber Knox, Michelle James, Dr Tyrell Cartwright, Dr Lee Borthwick, Professor Andrew FisherORCiD, Professor Jelena Mann, Professor Derek Mann, Professor Fiona OakleyORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
Objectives: NF-κB regulates genes that control inflammation, cell proliferation, differentiation and survival. Dysregulated NF-κB signalling alters normal skin physiology and deletion of cRel limits bleomycin induced skin fibrosis. This study investigates the role of cRel in modulating fibroblast phenotype in the context of systemic sclerosis (SSc). Methods: Fibrosis was assessed histologically in mice challenged with bleomycin to induce lung or skin fibrosis. RNA sequencing and pathway analysis was performed on wild type and Rel-/- murine lung and dermal fibroblasts. Functional assays examined fibroblast proliferation, migration and matrix production. cRel over-expression was investigated in human dermal fibroblasts. cRel immuno-staining was performed on lung and skin tissue sections from SSc patients and non-fibrotic controls. Results: cRel expression was elevated in murine lung and skin fibrosis models. Rel-/- mice were protected from developing pulmonary fibrosis. Soluble collagen production was significantly decreased in fibroblasts lacking cRel while proliferation and migration of these cells was significantly increased. cRel regulates genes involved in extracellular structure and matrix organisation. Positive cRel staining was observed in fibroblasts in human SSc skin and lung tissue. Over-expression of constitutively active cRel in human dermal fibroblasts increased expression of matrix genes. An NF-κB gene signature was identified in diffuse SSc skin and nuclear cRel expression was elevated in SSc skin fibroblasts. Conclusion: cRel regulates a pro-fibrogenic transcriptional programme in fibroblasts that may contribute to disease pathology. Targeting cRel signalling in fibroblasts of SSc patients could provide a novel therapeutic avenue to limit scar formation in this disease.
Author(s): Worrell J, Leslie J, Smith GR, Zaki M, Paish H, Knox A, James ML, Cartwright TN, OReily S, Kania G, Distler O, Distler J, Herrick A, Jeziorska M, Borthwick LA, Fisher AJ, Mann J, Mann DA, Oakley F
Publication type: Article
Publication status: Published
Journal: Rheumatology
Year: 2020
Volume: 59
Issue: 12
Pages: 3939-3951
Print publication date: 01/12/2020
Online publication date: 28/07/2020
Acceptance date: 24/04/2020
Date deposited: 25/08/2020
ISSN (print): 1462-0324
ISSN (electronic): 1462-0332
Publisher: Oxford University Press
URL: https://doi.org/10.1093/rheumatology/keaa272
DOI: 10.1093/rheumatology/keaa272
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