Abstract
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. 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. 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. 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.
Highlights
SSc is characterized by activation and accumulation of fibroblasts in multiple organs
Nuclear localization of cRel was observed in the epidermis and dermal fibroblasts of fibrotic skin, whereas cRel was visible in fibroblasts, epithelial cells and alveolar macrophages of the lung (Fig. 1A and B)
We previously reported that cRel knockout (RelÀ/À) mice are protected from developing dermal fibrosis [23]; the role of cRel in lung fibrosis had not previously been explored
Summary
SSc is characterized by activation and accumulation of fibroblasts in multiple organs. SSc fibroblasts secrete elevated levels of extracellular matrix (ECM) components: collagens, glycosaminoglycans and fibronectin, which promote scar formation and dermal thickening [1,2,3]. Fibroblast activation and differentiation into an alpha-smooth muscle actin (aSMA)-positive myofibroblast is associated with increased proliferation, aberrant secretion of ECM proteins and inflammatory chemokines [4, 5].
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