title: Abnormally differentiating keratinocytes in the epidermis of systemic sclerosis patients show enhanced secretion of CCN2 and S100A9.
abstract: Skin involvement with dermal fibrosis is a hallmark of systemic sclerosis (SSc), and keratinocytes may be critical regulators of fibroblast function through secretion of chemo-attracting agents, as well as through growth factors and cytokines influencing the phenotype and proliferation rate of fibroblasts. Epithelial-fibroblast interactions have an important role in fibrosis in general. We have characterized the SSc epidermis and asked whether SSc-injured epidermal cells release factors capable of promoting fibrosis. Our results show that the SSc epidermis is hypertrophic, and has altered expression of terminal differentiation markers involucrin, loricrin, and filaggrin. Multiplex profiling revealed that SSc epidermal explants release increased levels of CCN2 and S100A9. CCN2 induction was found to spread into the upper papillary dermis, whereas S100A9 was shown to induce fibroblast proliferation and to enhance fibroblast CCN2 expression via Toll-like receptor 4. These data suggest that the SSc epidermis provides an important source of pro-fibrotic CCN2 and proinflammatory S100A9 in SSc skin, and therefore contributes to the fibrosis and inflammation seen in the disease.
authors.affiliation: Centre for Rheumatology and Connective Tissue Diseases, Research Department of Inflammation, Division of Medicine, UCL-Medical School, London, UK. Electronic address: j.nikitorowicz-buniak@ucl.ac.uk.
authors.forename: Joanna
authors.initials: J
authors.lastname: Nikitorowicz-Buniak
authors.affiliation: Centre for Rheumatology and Connective Tissue Diseases, Research Department of Inflammation, Division of Medicine, UCL-Medical School, London, UK.
authors.forename: Xu
authors.initials: X
authors.lastname: Shiwen
authors.affiliation: Centre for Rheumatology and Connective Tissue Diseases, Research Department of Inflammation, Division of Medicine, UCL-Medical School, London, UK.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Denton
authors.affiliation: Centre for Rheumatology and Connective Tissue Diseases, Research Department of Inflammation, Division of Medicine, UCL-Medical School, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Abraham
authors.affiliation: Centre for Rheumatology and Connective Tissue Diseases, Research Department of Inflammation, Division of Medicine, UCL-Medical School, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Stratton
mesh_terms: D040502:Calgranulin B / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D020405:Dermis / Q000378:metabolism / Q000473:pathology; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005355:Fibrosis; D000091344:Filaggrin Proteins; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000378:metabolism*; D012867:Skin / Q000378:metabolism / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: C526317:CCN2 protein, human; D040502:Calgranulin B; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D055513:Connective Tissue Growth Factor; D017228:Hepatocyte Growth Factor