Critical role of the adhesion receptor DNAX accessory molecule-1 (DNAM-1) in the development of inflammation-driven dermal fibrosis in a mouse model of systemic sclerosis
- Jérôme Avouac1,2,
- Muriel Elhai2,
- Michal Tomcik3,4,
- Barbara Ruiz2,
- Manuel Friese5,
- Melanie Piedavent5,
- Marco Colonna6,
- Gunter Bernhardt7,
- André Kahan1,
- Gilles Chiocchia2,
- Jörg H W Distler3,
- Yannick Allanore1,2
- 1Rheumatology A Department, Paris Descartes University, Sorbonne Paris Cité, Cochin Hospital, Paris, France
- 2Cochin Institute, Paris Descartes University, INSERM U1016 and CNRS UMR8104, Paris, France
- 3Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
- 4Department of Rheumatology of the First Faculty of Medicine, Institute of Rheumatology and Connective Tissue Research Laboratory, Charles University in Prague, Czech Republic
- 5Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
- 6Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, USA
- 7Institute of Immunology, Hannover Medical School, Hannover, Germany
- Correspondence to Dr Jérôme Avouac, Rheumatology A Department, Paris Descartes University, Cochin Hospital, 27 rue du Faubourg Saint Jacques, Paris 75014, France;
- Accepted 20 October 2012
- Published Online First 17 November 2012
Objective To investigate the contribution of the adhesion receptor DNAX accessory molecule-1 (DNAM-1) in the development of dermal fibrosis on gene inactivation and targeted molecular strategies.
Methods Human skin expression of DNAM-1 was determined by immunohistochemistry. Mice deficient for DNAM-1 (dnam1−/−) and wild-type controls (dnam1+/+) were injected with bleomycin or NaCl. Infiltrating leucocytes, T cells, B cells and monocytes were quantified and inflammatory cytokines were measured in lesional skin of dnam1−/− and dnam1+/+ mice. The anti-fibrotic potential of a DNAM-1 neutralising monoclonal antibody (mAb) was evaluated in the mouse model of bleomycin-induced dermal fibrosis.
Results Overexpression of DNAM-1 was detected in the skin of patients with SSc (systemic sclerosis). Dnam1−/− mice were protected from bleomycin-induced dermal fibrosis with reduction of dermal thickening (75±5%, p=0.03), hydroxyproline content (46±8%, p=0.04) and myofibroblast counts (39±5%, p=0.01). Moreover, the number of T cells was significantly decreased in lesional skin of dnam1−/− mice (69±15%, p=0.0007). Dnam1−/− mice also displayed decreased levels of TNF-α and IL-6 in lesional skin. Consistent with the gene inactivation strategy, treatment of mice with DNAM-1 neutralising mAb prevented dermal fibrosis induced by bleomycin with reduction of dermal thickness (64±6%, p=0.002), hydroxyproline content (61±8%, p=0.004) and myofibroblast counts (83±12%, p=0.002).
Conclusions An inactivation gene strategy showed that DNAM-1 exerts profibrotic effects by controlling T cell activation and cytokine release. A molecular targeted strategy confirmed that DNAM-1 neutralising mAb has potent antifibrotic properties, supporting the hypothesis that inhibition of DNAM-1 might be a promising new approach for the treatment of SSc and potentially other related fibrotic diseases.