Abstract：
OBJECTIVE: Psoriasis is an autoimmune inflammatory skin disease, featuring microvascular abnormalities and elevated levels of bradykinin. Contact activation of Factor XII can initiate the plasma kallikrein-kinin cascade, producing inflammation and angioedema. The role of Factor XII in psoriasis is unknown.
METHODS: The effects of deficiency of Factor XII or its enzymatic substrate, prekallikrein, were examined in the imiquimod-induced mouse model of psoriasis. Skin microcirculation was assessed using intravital confocal microscopy and laser Doppler flowmeter. A novel antibody blocking Factor XII activation was evaluated for psoriasis prevention.
RESULTS: Expression of Factor XII was markedly up-regulated in human and mouse psoriatic skin. Genetic deletion of Factor XII or prekallikrein, attenuated imiquimod-induced psoriatic lesions in mice. Psoriatic induction increased skin microvascular blood perfusion, causing vasodilation, hyperpermeability and angiogenesis. It also promoted neutrophil-vascular interaction, inflammatory cytokine release and enhanced Factor XII / prekallikrein enzymatic activity with elevated bradykinin. Factor XII or prekallikrein deficiency ameliorated these microvascular abnormalities and abolished bradykinin increase. Antagonism of bradykinin B2 receptors reproduced the microvascular protection of Factor XII / prekallikrein deficiency, attenuated psoriatic lesions, and prevented protection by Factor XII / prekallikrein deficiency against psoriasis. Furthermore, treatment of mice with Factor XII antibody alleviated experimentally induced psoriasis and suppressed microvascular inflammation.
CONCLUSIONS: Activation of Factor XII promoted psoriasis via prekallikrein-dependent formation of bradykinin, which critically mediated psoriatic microvascular inflammation. Inhibition of contact activation represents a novel therapeutic strategy for psoriasis.
METHODS: The effects of deficiency of Factor XII or its enzymatic substrate, prekallikrein, were examined in the imiquimod-induced mouse model of psoriasis. Skin microcirculation was assessed using intravital confocal microscopy and laser Doppler flowmeter. A novel antibody blocking Factor XII activation was evaluated for psoriasis prevention.
RESULTS: Expression of Factor XII was markedly up-regulated in human and mouse psoriatic skin. Genetic deletion of Factor XII or prekallikrein, attenuated imiquimod-induced psoriatic lesions in mice. Psoriatic induction increased skin microvascular blood perfusion, causing vasodilation, hyperpermeability and angiogenesis. It also promoted neutrophil-vascular interaction, inflammatory cytokine release and enhanced Factor XII / prekallikrein enzymatic activity with elevated bradykinin. Factor XII or prekallikrein deficiency ameliorated these microvascular abnormalities and abolished bradykinin increase. Antagonism of bradykinin B2 receptors reproduced the microvascular protection of Factor XII / prekallikrein deficiency, attenuated psoriatic lesions, and prevented protection by Factor XII / prekallikrein deficiency against psoriasis. Furthermore, treatment of mice with Factor XII antibody alleviated experimentally induced psoriasis and suppressed microvascular inflammation.
CONCLUSIONS: Activation of Factor XII promoted psoriasis via prekallikrein-dependent formation of bradykinin, which critically mediated psoriatic microvascular inflammation. Inhibition of contact activation represents a novel therapeutic strategy for psoriasis.
摘要：
目的：银屑病是一种自身免疫性炎症性皮肤病，以微血管异常和缓激肽水平升高为特征。接触激活因子XII可以启动血浆激肽释放酶-激肽级联反应，产生炎症和血管性水肿。因子XII在银屑病中的作用尚不清楚。
方法：因子XII或其酶底物缺乏的影响，前激肽释放酶,在咪喹莫特诱导的银屑病小鼠模型中进行了检查。使用活体共聚焦显微镜和激光多普勒流量计评估皮肤微循环。评价了一种新的抗体阻断因子XII活化用于银屑病预防。
结果:因子XII的表达在人和小鼠银屑病皮肤中显著上调。因子XII或前激肽释放酶的遗传缺失，减毒咪喹莫特诱导的小鼠银屑病病变。银屑病诱导增加皮肤微血管血液灌注，引起血管舒张,高渗透性和血管生成。它还促进了中性粒细胞-血管的相互作用，炎性细胞因子释放和增强的因子XII/前激肽释放酶活性与升高的缓激肽。因子XII或前激肽释放酶缺乏改善了这些微血管异常并消除了缓激肽的增加。缓激肽B2受体的拮抗作用再现了因子XII/前激肽释放酶缺乏的微血管保护作用，银屑病病变减弱，并防止因子XII/前激肽释放酶缺乏对银屑病的保护作用。此外，用因子XII抗体治疗小鼠减轻了实验诱导的牛皮癣并抑制了微血管炎症。
结论：因子XII的激活通过前激肽释放酶依赖性缓激肽的形成促进银屑病，关键介导银屑病微血管炎症。抑制接触激活代表了银屑病的新型治疗策略。
方法：因子XII或其酶底物缺乏的影响，前激肽释放酶,在咪喹莫特诱导的银屑病小鼠模型中进行了检查。使用活体共聚焦显微镜和激光多普勒流量计评估皮肤微循环。评价了一种新的抗体阻断因子XII活化用于银屑病预防。
结果:因子XII的表达在人和小鼠银屑病皮肤中显著上调。因子XII或前激肽释放酶的遗传缺失，减毒咪喹莫特诱导的小鼠银屑病病变。银屑病诱导增加皮肤微血管血液灌注，引起血管舒张,高渗透性和血管生成。它还促进了中性粒细胞-血管的相互作用，炎性细胞因子释放和增强的因子XII/前激肽释放酶活性与升高的缓激肽。因子XII或前激肽释放酶缺乏改善了这些微血管异常并消除了缓激肽的增加。缓激肽B2受体的拮抗作用再现了因子XII/前激肽释放酶缺乏的微血管保护作用，银屑病病变减弱，并防止因子XII/前激肽释放酶缺乏对银屑病的保护作用。此外，用因子XII抗体治疗小鼠减轻了实验诱导的牛皮癣并抑制了微血管炎症。
结论：因子XII的激活通过前激肽释放酶依赖性缓激肽的形成促进银屑病，关键介导银屑病微血管炎症。抑制接触激活代表了银屑病的新型治疗策略。
