Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma
Open accessAbstract
In systemic sclerosis (SSc), a common and aetiologically mysterious form of scleroderma (defined as pathological fibrosis of the skin), previously healthy adults acquire fibrosis of the skin and viscera in association with autoantibodies. Familial recurrence is extremely rare and causal genes have not been identified. Although the onset of fibrosis in SSc typically correlates with the production of autoantibodies, whether they contribute to disease pathogenesis or simply serve as a marker of disease remains controversial and the mechanism for their induction is largely unknown. The study of SSc is hindered by a lack of animal models that recapitulate the aetiology of this complex disease. To gain a foothold in the pathogenesis of pathological skin fibrosis, we studied stiff skin syndrome (SSS), a rare but tractable Mendelian disorder leading to childhood onset of diffuse skin fibrosis with autosomal dominant inheritance and complete penetrance. We showed previously that SSS is caused by heterozygous missense mutations in the gene (FBN1) encoding fibrillin-1, the main constituent of extracellular microfibrils. SSS mutations all localize to the only domain in fibrillin-1 that harbours an Arg-Gly-Asp (RGD) motif needed to mediate cell-matrix interactions by binding to cell-surface integrins. Here we show that mouse lines harbouring analogous amino acid substitutions in fibrillin-1 recapitulate aggressive skin fibrosis that is prevented by integrin-modulating therapies and reversed by antagonism of the pro-fibrotic cytokine transforming growth factor β (TGF-β). Mutant mice show skin infiltration of pro-inflammatory immune cells including plasmacytoid dendritic cells, T helper cells and plasma cells, and also autoantibody production; these findings are normalized by integrin-modulating therapies or TGF-β antagonism. These results show that alterations in cell-matrix interactions are sufficient to initiate and sustain inflammatory and pro-fibrotic programmes and highlight new therapeutic strategies.
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In a genetic mouse model for SSc, antibodies against integrin α5β1 and integrin α5β3 inhibit skin fibrosis.
“In a genetic mouse model for SSc (characterized by a mutation in fibrilin) antibodies against integrin α5β1 and integrin α5β3 inhibit skin fibrosis (202).”
From Unraveling SSc Pathophysiology; The Myofibroblast (2018) · cites this paper as [202]
The effects of anti-integrin α5β1/α5β3 antibodies are mimicked by a TGFβ-inhibiting antibody, suggesting these effects possibly run via inhibition of TGFβ activation.
“The effects of these antibodies are mimicked by a TGFβ inhibiting antibody, illustrating that these effects possibly run via inhibition of TGFβ activation.”
From Unraveling SSc Pathophysiology; The Myofibroblast (2018) · cites this paper as [202]
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- Authors
- Gerber, E. E., Gallo, E. M., Fontana, S. C., Davis, E. C., Wigley, F. M., Huso, D. L., & Dietz, H. C.
- Affiliations
- Johns Hopkins University (US)
- McGill University (CA)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Dietz, Harry C.
- Venue
- Nature
- Published
- 2013-10-09
- Volume
- 503
- Issue
- 7474
- Pages
- 126-130
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3992987
- OpenAlex
- W2065840402
- Cited by
- 190
- References
- 40
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 9 · 2023: 8 · 2022: 10 · 2021: 9 · 2020: 10 · 2019: 16 · 2018: 21 · 2017: 19 · 2016: 18 · 2015: 29 · 2014: 24 · 2013: 3
- FWCI
- 18.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Scleroderma Foundation
- Scleroderma Research Foundation
- National Institute of General Medical Sciences (T32GM007814)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR041135, R01-AR-41135, P01AR049698)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Systemic Sclerosis and Related Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- systemic sclerosis, stiff skin syndrome, fibrillin-1, integrin signaling, skin fibrosis, autoimmunity, plasmacytoid dendritic cells, TGF-beta, RGD motif, FBN1 mutations, mouse model, fibroblast activation, ERK signaling, autoantibodies, extracellular matrix
- MeSH terms
- Fibrillins, Fibrillin-1, Animals, Antibodies, Antinuclear, Contracture, Dendritic Cells, Female, Fibrosis, T-Lymphocytes, Helper-Inducer, Male, Microfilament Proteins, Plasma Cells, Scleroderma, Systemic, Skin Diseases, Genetic, Autoimmunity, Integrins, Transforming Growth Factor beta, Amino Acid Substitution, Mutation, Missense, Amino Acid Motifs, Mice, Adipokines, Antibodies, Neutralizing
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