Article Text

PDF
OP0227 Critical Role of the Adhesion Receptor DNAX Accessory Molecule-1 (DNAM-1) in the Development of Inflammation-Driven Dermal Fibrosis in Mouse Model of Systemic Sclerosis
  1. J. Avouac1,2,
  2. M. Elhai2,
  3. M. Tomcik3,
  4. M. Friese4,
  5. M. Colonna5,
  6. G. Bernhardt6,
  7. A. Kahan1,
  8. G. Chiocchia2,
  9. J. Distler7,
  10. Y. Allanore1,2
  1. 1Rheumatology A, Paris Descartes University, Cochin Hospital
  2. 2INSERM U1016, Cochin Institute, Paris, France
  3. 3Institute of Rheumatology and Connective Tissue Research Laboratory, Department of Rheumatology of the First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
  4. 4Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
  5. 5Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States
  6. 6Institute of Immunology, Hannover Medical School, Hannover
  7. 7Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany

Abstract

Background DNAX accessory molecule 1 (DNAM-1) is an adhesion factor involved in the adhesion and co-stimulation of T cells. DNAM-1 has been recently identified as a genetic susceptibility factor to systemic sclerosis (SSc) and also to other autoimmune diseases.

Objectives Our aim was to investigate the contribution of DNAM-1 in the development of dermal fibrosis upon gene inactivation and targeted molecular strategies.

Methods Human skin expression of DNAM-1 was determined by immunohistochemistry. Mice deficient for DNAM-1 (dnam1-/-) and wildtype controls (dnam1+/+) were injected with bleomycin or NaCl. Infiltrating leukocytes, T cells, B cells and monocytes were quantified respectively on hematoxylin and eosin stained sections and by immunohistochemistry for CD3, CD22 and CD68. Inflammatory cytokines were measured in lesional skin of dnam1-/- and dnam1+/+ mice by flow cytometry. The anti-fibrotic potential of a DNAM-1 neutralizing monoclonal antibody (mAb) was also evaluated in the mouse model of bleomycin-induced dermal fibrosis.

Results Overexpression of DNAM-1 was detected in the lesional skin of SSc patients, especially in perivascular inflammatory cells. Dnam1-/- mice were protected from bleomycin-induced dermal fibrosis with reduced dermal thickening (75±5% reduction, p=0.02), hydroxyproline content (46±8% decrease, p=0.02) and myofibroblast counts (39±5% reduction, p=0.04). The numbers infiltrating T cells were decreased in lesional skin of dnam1-/- mice by 69±15% (p=0.009). The number of B cells and monocytes was not significantly different in dnam1-/- and dnam1+/+ mice upon bleomycin challenge. Moreover, dnam1-/- mice displayed in lesional skin decreased levels of inflammatory cytokines, such as IL-6 (59±12%, p=0.001 decrease), and TNFα (60±15%, p=0.03). Treatment with anti-DNAM-1 mAb significantly reduced dermal thickening by 64±6% (p=0.01), hydroxyproline content by 61±8% (p=0.001), and myofibroblast counts by 83±12% (P=0.03). These results were similar to those observed in DNAM-1 deficient mice.

Conclusions We demonstrate with two complementary approaches that inhibition of DNAM-1 significantly ameliorates dermal inflammation-driven fibrosis. DNAM-1 displays profibrotic effects by promoting the infiltration of T cells, into lesional skin and by stimulating the release of inflammatory cytokines. In addition, molecular targeting strategy using a DNAM-1 neutralizing mAb confirmed potent antifibrotic properties of DNAM-1 inhibition. Our findings might have direct translational implications and inhibition of DNAM-1 might be a promising new approach for the treatment of SSc and potentially other fibrotic diseases.

Disclosure of Interest None Declared

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.