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

Worrell, Julie C, Leslie, Jack, Smith, Graham R, Zaki, Marco Y W, Paish, Hannah L, Knox, Amber, James, Michelle L, Cartwright, Tyrell N, O'Reilly, Steven, Kania, Gabriela, Distler, Oliver, Distler, Jörg H W, Herrick, Ariane L, Jeziorska, Maria, Borthwick, Lee A, Fisher, Andrew J, Mann, Jelena, Mann, Derek A and Oakley, Fiona (2020) cRel expression regulates distinct transcriptional and functional profiles driving fibroblast matrix production in systemic sclerosis. Rheumatology, 59 (12). pp. 3939-3951. ISSN 1462-0324

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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 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 overexpression was investigated in human dermal fibroblasts. cRel immunostaining 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 organization. Positive cRel staining was observed in fibroblasts in human SSc skin and lung tissue. Overexpression 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.

Item Type: Article
Additional Information: Funding information: The research leading to these results has received funding from an Arthritis Research UK research grant 20812 awarded to F.O., J.M. and D.A.M., and Medical Research Council program Grants MR/K0019494/ 1 to D.A.M., J.M. and F.O., and Grant MR/R023026/1 to D.A.M., J.M., L.A.B. and F.O. The research was supported by the National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle Hospitals National Health Service Foundation Trust and Newcastle University.
Uncontrolled Keywords: cRel, extracellular-matrix, fibroblasts, lung, skin, systemic sclerosis
Subjects: B200 Pharmacology, Toxicology and Pharmacy
C100 Biology
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: Rachel Branson
Date Deposited: 04 May 2022 14:26
Last Modified: 04 May 2022 14:30

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