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cRel expression regulates distinct transcriptional and functional profiles driving fibroblast matrix production in systemic sclerosis

Lookup NU author(s): Dr Julie Worrell, Dr Jack Leslie, Dr Graham Smith, Marco Zaki, Hannah Paish, Amber Knox, Michelle James, Dr Tyrell Cartwright, Dr Lee Borthwick, Professor Andrew Fisher, Professor Jelena Mann, Professor Derek Mann, Professor Fiona Oakley

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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


Abstract

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.


Publication metadata

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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