RESUMO
Von Willebrand factor (VWF), a key player in hemostasis, is increasingly recognized as a proinflammatory protein. Here, we found a massive accumulation of VWF in skin biopsies of patients suffering from immune complex (IC)-mediated vasculitis (ICV). To clarify the impact of VWF on cutaneous inflammation, we induced experimental ICV either in mice treated with VWF-blocking antibodies or in VWF(-/-) mice. Interference with VWF led to a significant inhibition of the cutaneous inflammatory response. We confirmed the major findings in irritative contact dermatitis, a second model of cutaneous inflammation. In vivo imaging of cutaneous inflammation in the dorsal skinfold chamber revealed unaffected leukocyte rolling on anti-VWF treatment. However, we identified that reduced leukocyte recruitment is accompanied by reduced vascular permeability. Although VWF-mediated neutrophil recruitment to the peritoneum was described to require the VWF receptor on platelets (glycoprotein Ibα (GPIbα)), the VWF/GPIbα axis was dispensable for cutaneous inflammation. As assessed in tail bleeding assays, we could exclude interference of VWF blockade with hemostasis. Of particular importance, anti-VWF treatment was effective both in prophylactic and therapeutic administration. Thus, VWF represents a promising target for the treatment of cutaneous inflammation, e.g., leukocytoclastic vasculitis.
Assuntos
Anticorpos Bloqueadores/farmacologia , Dermatite de Contato/tratamento farmacológico , Doenças do Complexo Imune/tratamento farmacológico , Vasculite Leucocitoclástica Cutânea/tratamento farmacológico , Fator de von Willebrand/antagonistas & inibidores , Fator de von Willebrand/imunologia , Animais , Anticorpos Bloqueadores/imunologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Quimiotaxia de Leucócito/imunologia , Dermatite de Contato/imunologia , Modelos Animais de Doenças , Humanos , Doenças do Complexo Imune/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Complexo Glicoproteico GPIb-IX de Plaquetas/imunologia , Vasculite Leucocitoclástica Cutânea/imunologia , Fator de von Willebrand/genéticaRESUMO
The melanocortin-1 receptor (MC1 ) - being most abundantly expressed in the skin by melanocytes - has a physiological role for melanin pigmentation in many vertebrate species. MC1 has also been implicated in regulation of skin inflammation as this receptor is detectable in the majority of non-melanocytic cell types and its ligand α-melanocyte-stimulating hormone (α-MSH) exerts immunoregulatory and anti-inflammatory effects. However, in vivo studies on mice with targeted disruption of MC1 have been missing in the context of skin inflammation until recently. Wolnicka-Glubisz et al. now reported that the course of ultraviolet (UV)-induced inflammation, contact hypersensitivity, neonatal immune tolerance and UV-induced immunosuppression is similar in MC1 signal-deficient (C57BL/6-Mc1r(e/e)) and wild-type mice. These unexpected findings are supported by own observations in experimentally induced immune-complex-mediated vasculitis: Mc1r(e/e) mice exhibited a similar extent of the reverse passive cutaneous Arthus reaction compared with wild-type animals. Future studies are thus needed to clarify whether these findings are due to limitations in the chosen mouse model and/or point to additional MC subtypes that may regulate inflammatory and immune responses in the skin.