Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma

This article has been updated


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 autoantibodies1. 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 unknown2. 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 microfibrils3. 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 integrins3. 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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: SSS mouse models show skin fibrosis.
Figure 2: Integrin-modulating interventions prevent skin fibrosis.
Figure 3: A panspecific TGF-β-neutralizing antibody reverses established skin fibrosis.
Figure 4: Immunological abnormalities in SSS mice are prevented by integrin-modulating therapies.

Change history

  • 06 November 2012

    Figure 4a was corrected.


  1. Mayes, M. D. et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 48, 2246–2255 (2003)

    Article  Google Scholar 

  2. Harris, M. L. & Rosen, A. Autoimmunity in scleroderma: the origin, pathogenetic role, and clinical significance of autoantibodies. Curr. Opin. Rheumatol. 15, 778–784 (2003)

    CAS  Article  Google Scholar 

  3. Loeys, B. L. et al. Mutations in fibrillin-1 cause congenital scleroderma: stiff skin syndrome. Sci. Transl. Med. 2, 23ra20 (2010)

    CAS  Article  Google Scholar 

  4. Varga, J. & Pasche, B. Transforming growth factor β as a therapeutic target in systemic sclerosis. Nature Rev. Rheumatol. 5, 200–206 (2009)

    CAS  Article  Google Scholar 

  5. Doyle, J. J., Gerber, E. E. & Dietz, H. C. Matrix-dependent perturbation of TGF-β signaling and disease. FEBS Lett. 586, 2003–2015 (2012)

    CAS  Article  Google Scholar 

  6. Lindsay, M. E. & Dietz, H. C. Lessons on the pathogenesis of aneurysm from heritable conditions. Nature 473, 308–316 (2011)

    ADS  CAS  Article  Google Scholar 

  7. Reynolds, L. E. et al. Accelerated re-epithelialization in β3-integrin-deficient mice is associated with enhanced TGF-β1 signaling. Nature Med. 11, 167–174 (2005)

    CAS  Article  Google Scholar 

  8. Munger, J. S. & Sheppard, D. Cross talk among TGF-β signaling pathways, integrins, and the extracellular matrix. Cold Spring Harb. Perspect. Biol. 3, a005017 (2011)

    Article  Google Scholar 

  9. Swiecki, M. & Colonna, M. Unraveling the functions of plasmacytoid dendritic cells during viral infections, autoimmunity, and tolerance. Immunol. Rev. 234, 142–162 (2010)

    CAS  Article  Google Scholar 

  10. van Rooij, E. et al. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc. Natl Acad. Sci. USA 105, 13027–13032 (2008)

    ADS  CAS  Article  Google Scholar 

  11. Maurer, B. et al. MicroRNA-29, a key regulator of collagen expression in systemic sclerosis. Arthritis Rheum. 62, 1733–1743 (2010)

    CAS  Article  Google Scholar 

  12. Hall, J. C. & Rosen, A. Type I interferons: crucial participants in disease amplification in autoimmunity. Nature Rev. Rheumatol. 6, 40–49 (2010)

    CAS  Article  Google Scholar 

  13. Sakkas, L. I., Chikanza, I. C. & Platsoucas, C. D. Mechanisms of disease: the role of immune cells in the pathogenesis of systemic sclerosis. Nature Clin. Pract. Rheumatol. 2, 679–685 (2006)

    CAS  Article  Google Scholar 

  14. Fujimoto, M. et al. CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse. J. Clin. Invest. 109, 1453–1462 (2002)

    Article  Google Scholar 

  15. Bona, C. & Rothfield, N. Autoantibodies in scleroderma and tight skin mice. Curr. Opin. Immunol. 6, 931–937 (1994)

    CAS  Article  Google Scholar 

  16. Brakebusch, C. et al. Skin and hair follicle integrity is crucially dependent on β1 integrin expression on keratinocytes. EMBO J. 19, 3990–4003 (2000)

    CAS  Article  Google Scholar 

  17. Liu, S. et al. Loss of β1 integrin in mouse fibroblasts results in resistance to skin scleroderma in a mouse model. Arthritis Rheum. 60, 2817–2821 (2009)

    CAS  Article  Google Scholar 

  18. van Helden, S. F. et al. A critical role for prostaglandin E2 in podosome dissolution and induction of high-speed migration during dendritic cell maturation. J. Immunol. 177, 1567–1574 (2006)

    CAS  Article  Google Scholar 

  19. Zou, W. et al. Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nature Med. 7, 1339–1346 (2001)

    CAS  Article  Google Scholar 

  20. Ding, C., Cai, Y., Marroquin, J., Ildstad, S. T. & Yan, J. Plasmacytoid dendritic cells regulate autoreactive B cell activation via soluble factors and in a cell-to-cell contact manner. J. Immunol. 183, 7140–7149 (2009)

    CAS  Article  Google Scholar 

  21. Jego, G. et al. Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6. Immunity 19, 225–234 (2003)

    CAS  Article  Google Scholar 

  22. Fleming, J. N. et al. Capillary regeneration in scleroderma: stem cell therapy reverses phenotype. PLoS ONE 3, e1452 (2008)

    ADS  Article  Google Scholar 

  23. Saas, P. & Perruche, S. Functions of TGF-β-exposed plasmacytoid dendritic cells. Crit. Rev. Immunol. 32, 529–553 (2012)

    CAS  Article  Google Scholar 

  24. Bratke, K., Klein, C., Kuepper, M., Lommatzsch, M. & Virchow, J. C. Differential development of plasmacytoid dendritic cells in Th1- and Th2-like cytokine milieus. Allergy 66, 386–395 (2011)

    CAS  Article  Google Scholar 

  25. Dardalhon, V. et al. IL-4 inhibits TGF-β-induced Foxp3+ T cells and, together with TGF-β, generates IL-9+ IL-10+ Foxp3 effector T cells. Nature Immunol. 9, 1347–1355 (2008)

    CAS  Article  Google Scholar 

  26. Nakerakanti, S. S., Bujor, A. M. & Trojanowska, M. CCN2 is required for the TGF-β induced activation of Smad1–Erk1/2 signaling network. PLoS ONE 6, e21911 (2011)

    ADS  CAS  Article  Google Scholar 

  27. Chen, Y. et al. Heparan sulfate-dependent ERK activation contributes to the overexpression of fibrotic proteins and enhanced contraction by scleroderma fibroblasts. Arthritis Rheum. 58, 577–585 (2008)

    CAS  Article  Google Scholar 

  28. Asano, Y. et al. Increased expression of integrin αvβ3 contributes to the establishment of autocrine TGF-β signaling in scleroderma fibroblasts. J. Immunol. 175, 7708–7718 (2005)

    CAS  Article  Google Scholar 

  29. Watarai, H. et al. PDC-TREM, a plasmacytoid dendritic cell-specific receptor, is responsible for augmented production of type I interferon. Proc. Natl Acad. Sci. USA 105, 2993–2998 (2008)

    ADS  CAS  Article  Google Scholar 

  30. Kawai, T. & Akira, S. TLR signaling. Cell Death Differ. 13, 816–825 (2006)

    CAS  Article  Google Scholar 

  31. Judge, D. P. et al. Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. J. Clin. Invest. 114, 172–181 (2004)

    CAS  Article  Google Scholar 

  32. Castelino, F. V. et al. Amelioration of dermal fibrosis by genetic deletion or pharmacologic antagonism of lysophosphatidic acid receptor 1 in a mouse model of scleroderma. Arthritis Rheum. 63, 1405–1415 (2011)

    CAS  Article  Google Scholar 

  33. HogenEsch, H. et al. Expression of chitinase-like proteins in the skin of chronic proliferative dermatitis (cpdm/cpdm) mice. Exp. Dermatol. 15, 808–814 (2006)

    CAS  Article  Google Scholar 

  34. Davis, E. C. et al. Remodeling of elastic fiber components in scleroderma skin. Connect. Tissue Res. 40, 113–121 (1999)

    ADS  CAS  Article  Google Scholar 

  35. Garfield, A. S. Derivation of primary mouse embryonic fibroblast (PMEF) cultures. Methods Mol. Biol. 633, 19–27 (2010)

    CAS  Article  Google Scholar 

  36. Lakos, G. et al. Animal models of scleroderma. Methods Mol. Med. 102, 377–393 (2004)

    PubMed  Google Scholar 

  37. Gehrie, E. et al. Plasmacytoid dendritic cells in tolerance. Methods Mol. Biol. 677, 127–147 (2011)

    CAS  Article  Google Scholar 

  38. Pampori, N. et al. Mechanisms and consequences of affinity modulation of integrin αVβ3 detected with a novel patch-engineered monovalent ligand. J. Biol. Chem. 274, 21609–21616 (1999)

    CAS  Article  Google Scholar 

  39. Kiosses, W. B. et al. Rac recruits high-affinity integrin αvβ3 to lamellipodia in endothelial cell migration. Nature Cell Biol. 3, 316–320 (2001)

    CAS  Article  Google Scholar 

Download references


We thank those who contributed skin biopsies to this study and those who provided reagents for this study, including S. Shattil, K. Flanders, C. J. Thomas, S. Patnaik and J. J. Marugan. This work was supported by grants to H.C.D. from the Scleroderma Research Foundation, the National Institutes of Health (RO1-AR41135 and PO1-AR049698), the National Marfan Foundation, the Smilow Center for Marfan Syndrome Research, and the Howard Hughes Medical Institute.

Author information

Authors and Affiliations



E.E.G., E.M.G. and H.C.D. designed experiments and interpreted the data. E.M.G. performed enzyme-linked immunosorbent assays. F.M.W. obtained skin samples from patients (the Scleroderma Center of Johns Hopkins University School of Medicine) and provided guidance and clinical expertise. S.C.F. assisted in drug trials in vivo and in the collection of mouse sera. E.C.D. performed electron microscopy. E.E.G. generated mouse models and performed all other experiments. D.L.H. aided in complete blood count analysis, mouse surgery, and histopathology. E.E.G. and H.C.D. wrote the paper.

Corresponding author

Correspondence to Harry C. Dietz.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-16. This file was replaced on 6 November 2013. (PDF 15128 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gerber, E., Gallo, E., Fontana, S. et al. Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma. Nature 503, 126–130 (2013).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing