Factor XII and prekallikrein promote microvascular inflammation and psoriasis in mice

Author:

Zhang Yurong1,Chen Zengrong1,Guo Junyan12,Wan Qing1,Zhang Yingjie1,Li Huihui1,Rao Haojie1,Yang Jianfeng1,Xu Pengfei1ORCID,Chen Hong1,Wang Miao134ORCID

Affiliation:

1. State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China

2. College of Life Science Zhejiang Normal University Jinhua City China

3. Clinical Pharmacology Center, Fuwai Hospital, National Center for Cardiovascular Diseases Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China

4. National Health Commission Key Laboratory of Cardiovascular Regenerative Medicine, Central China Subcenter of National Center for Cardiovascular Diseases, Henan Cardiovascular Disease Center, Fuwai Central‐China Cardiovascular Hospital Central China Fuwai Hospital of Zhengzhou University Zhengzhou China

Abstract

Background and PurposePsoriasis 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.Experimental ApproachThe 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.Key ResultsExpression 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.Conclusion and ImplicationsActivation 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.

Funder

National Key Research and Development Program of China

National Natural Science Foundation of China

Publisher

Wiley

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