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.

TY - JOUR

T1 - 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.

AU - Avouac, Jérôme

AU - Elhai, Muriel

AU - Tomcik, Michal

AU - Ruiz, Barbara

AU - Friese, Manuel A.

AU - Piedavent, Melanie

AU - Colonna, Marco

AU - Bernhardt, Gunter

AU - Kahan, André

AU - Chiocchia, Gilles

AU - Distler, Jörg H W

AU - Allanore, Yannick

PY - 2012

Y1 - 2012

N2 - 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-? 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.

AB - 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-? 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.

M3 - SCORING: Journal article

VL - 72(6)

SP - 1089

EP - 1098

JO - ANN RHEUM DIS

JF - ANN RHEUM DIS

SN - 0003-4967

ER -