Abstract
Systemic sclerosis (SSc) is a multisystem connective tissue disease characterized
by three cardinal pathological features, such as autoimmunity/inflammation, vasculopathy
and extensive organ fibrosis. Therefore, numerous interests have been put on the roles
of immune cells, vascular cells (endothelial cells and pericytes/vascular smooth muscle
cells) and interstitial fibroblasts as well as their precursors in the field of SSc
research. However, recent studies with clinical samples and animal models have drawn
much attention to the potential role of epithelial cells as a member of critical drivers
and/or modifiers in the pathogenesis of SSc. Indeed, phenotypically altered epithelial
cells possibly explain the selective organ fibrosis in the skin, esophagus and lung,
the origin of autoimmunity and Köbner phenomenon-associated localized scleroderma-like
lesions, the mechanisms of which had remained unknown in the canonical idea of SSc
pathogenesis. This article overviews the recent progress in understanding the contribution
of epithelial cells to the pathogenesis of SSc. Although further studies are required
to confirm the potential role of epithelial cells in SSc development, this notion
may provide us with a missing piece of the puzzle to solve the unanswered questions
in the pathogenesis of SSc.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of Dermatological ScienceAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Systemic sclerosis.J. Dermatol. 2018; 45: 128-138
- Familial occurrence frequencies and relative risks for systemic sclerosis (scleroderma) in three United States cohorts.Arthritis Rheum. 2001; 44: 1359-1362
- Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies.Arthritis Rheum. 2003; 48: 1956-1963
- The role of genetics and epigenetics in the pathogenesis of systemic sclerosis.Nat. Rev. Rheumatol. 2014; 10: 671-681
- Endothelial cell apoptosis in systemic sclerosis is induced by antibody-dependent cell-mediated cytotoxicity via CD95.Arthritis Rheum. 2000; 43: 2550-2562
- Gammadelta receptor bearing T cells in scleroderma: enhanced interaction with vascular endothelial cells in vitro.Clin. Immunol. 1999; 91: 188-195
- Vasculopathy in scleroderma.Semin. Immunopathol. 2015; 37: 489-500
- Fibrosis, vascular activation, and immune abnormalities resembling systemic sclerosis in bleomycin-treated fli-1-haploinsufficient mice.Arthritis Rheumatol. 2015; 67: 517-526
- Increased expression of chemerin in endothelial cells due to Fli1 deficiency may contribute to the development of digital ulcers in systemic sclerosis.Rheumatol. Oxford (Oxford). 2015; 54: 1308-1316
- Altered monocyte and fibrocyte phenotype and function in scleroderma interstitial lung disease: reversal by caveolin-1 scaffolding domain peptide.Fibrogenesis Tissue Rep. 2011; 4: 15
- Partially evoked epithelial-mesenchymal transition (EMT) is associated with increased TGFβ signaling within lesional scleroderma skin.PLoS One. 2015; 10e0134092
- Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis.Ann. Rheum. Dis. 2017; 76: 924-934
- Myofibroblasts in murine cutaneous fibrosis originate from adiponectin-positive intradermal progenitors.Arthritis Rheumatol. 2015; 67: 1062-1073
- Localization of endothelin-1 and its binding sites in scleroderma skin.J. Rheumatol. 1994; 21: 1268-1276
- Elevated expression of type VII collagen in the skin of patients with systemic sclerosis. Regulation by transforming growth factor-beta.J. Clin. Invest. 1994; 93: 1709-1715
- Overexpression of monocyte chemoattractant protein 1 in systemic sclerosis: role of platelet-derived growth factor and effects on monocyte chemotaxis and collagen synthesis.Arthritis Rheum. 2001; 44: 2665-2678
- The differential expression of VEGF, VEGFR-2, and GLUT-1 proteins in disease subtypes of systemic sclerosis.Hum. Pathol. 2006; 37: 190-197
- Expression of interleukin-21 receptor in epidermis from patients with systemic sclerosis.Arthritis Rheum. 2005; 52: 856-864
- Proteomic analysis of scleroderma lesional skin reveals activated wound healing phenotype of epidermal cell layer.Rheumatol. Oxford (Oxford). 2008; 47: 1754-1760
- Epithelial cells promote fibroblast activation via IL-1alpha in systemic sclerosis.J. Invest. Dermatol. 2010; 130: 2191-2200
- Abnormally differentiating keratinocytes in the epidermis of systemic sclerosis patients show enhanced secretion of CCN2 and S100A9.J. Invest. Dermatol. 2014; 134: 2693-2702
- Epigenetic suppression of Fli1, a potential predisposing factor in the pathogenesis of systemic sclerosis.Int. J. Biochem. Cell Biol. 2015; 67: 86-91
- Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: possible roles in scleroderma.J. Exp. Med. 2017; 214: 1129-1151
- Association between enhanced type I collagen expression and epigenetic repression of the FLI1 gene in scleroderma fibroblasts.Arthritis Rheum. 2006; 54: 2271-2279
- Endothelial Fli1 deficiency impairs vascular homeostasis: a role in scleroderma vasculopathy.Am. J. Pathol. 2010; 176: 1983-1998
- Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis.N. Engl. J. Med. 2014; 370: 433-443
- Decreased expression of neuropilin-1 as a novel key factor contributing to peripheral microvasculopathy and defective angiogenesis in systemic sclerosis.Ann. Rheum. Dis. 2016; 75: 1541-1549
- Simultaneous downregulation of KLF5 and Fli1 is a key feature underlying systemic sclerosis.Nat. Commun. 2014; 5: 5797
- Endothelin receptor blockade ameliorates vascular fragility in endothelial cell-specific fli-1-knockout mice by increasing fli-1 DNA binding ability.Arthritis Rheumatol. 2015; 67: 1335-1344
- Fli1 deficiency contributes to the downregulation of endothelial protein C receptor in systemic sclerosis: a possible role in prothrombotic conditions.Br. J. Dermatol. 2016; 174: 338-347
- Cyclophosphamide pulse therapy normalizes vascular abnormalities in a mouse model of systemic sclerosis vasculopathy.J. Invest. Dermatol. 2018;
- Scleroderma keratinocytes promote fibroblast activation independent of transforming growth factor beta.Rheumatology Oxford (Oxford). 2017; 56: 1970-1981
- Galectin-7 in the control of epidermal homeostasis after injury.Mol. Biol. Cell. 2008; 19: 5541-5549
- A potential contribution of decreased galectin-7 expression in stratified epithelia to the development of cutaneous and esophageal manifestations in systemic sclerosis.Exp. Dermatol. 2019;
- Diagnostic criteria, severity classification and guidelines of localized scleroderma.J. Dermatol. 2018; 45: 755-780
- Systemic sclerosis complicated with localized scleroderma-like lesions induced by Kobner phenomenon.J. Dermatol. Sci. 2018; 89: 282-289
- Histological features of localized scleroderma’ en coup de sabre’: a study of 16 cases.J. Eur. Acad. Dermatol. Venereol. 2014; 28: 1805-1810
- IL-1 induces vesicular secretion of IL-6 without degranulation from human mast cells.J. Immunol. 2003; 171: 4830-4836
- S100 proteins in the epidermis.J. Invest. Dermatol. 2004; 123: 23-33
- S100A7 (psoriasin) inhibits human epidermal differentiation by enhanced IL-6 secretion through IkappaB/NF-kappaB signalling.Exp. Dermatol. 2016; 25: 636-641
- In situ localization of interleukin-6 in normal skin and atrophic cutaneous disease.Int. Arch. Allergy Immunol. 1992; 99: 44-49
- Critical contribution of the interleukin-6/signal transducer and activator of transcription 3 axis to vasculopathy associated with systemic sclerosis.J. Dermatol. 2017; 44: 967-971
- Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial.Lancet. 2016; 387: 2630-2640
- Active proliferation of telangiectases in skin of patients with progressive systemic sclerosis (PSS).Arch. Dermatol. Res. 1986; 279: 8-11
- Psoriasin (S100A7) promotes stress-induced angiogenesis.Br. J. Dermatol. 2016; 175: 1263-1273
- Pitting scars in progressive systemic sclerosis.Dermatology. 1993; 187: 104-108
- Differential expression of CRABP II, psoriasin and cytokeratin 1 mRNA in human skin diseases.Arch. Dermatol. Res. 1996; 288: 426-430
- Little peptide, big effects: the role of LL-37 in inflammation and autoimmune disease.J. Immunol. 2013; 191: 4895-4901
- A potential contribution of antimicrobial peptide LL-37 to tissue fibrosis and vasculopathy in systemic sclerosis.Br. J. Dermatol. 2016; 175: 1195-1203
- Phototherapy in systemic sclerosis: review.Photodermatol. Photoimmunol. Photomed. 2017; 33: 296-305
Biography
Yoshihide Asano received his MD at The University of Tokyo in 1998 and his PhD at Graduate School of Medicine and Faculty of Medicine, The University of Tokyo in 2004. He trained as a Postdoctoral Fellow under Prof. Maria Trojanowska at Medical University of South Carolina from 2006 to 2008. In 2009, he became an Assistant Professor in the Department of Dermatology at Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, where he became an Associate Professor in 2015. He has published more than 330 scientific publications. His research interest is collagen disease, especially systemic sclerosis.
Article info
Publication history
Published online: May 01, 2019
Accepted:
April 26,
2019
Received:
April 21,
2019
Identification
Copyright
© 2019 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.
