Factor XII and prekallikrein promote microvascular inflammation and psoriasis in mice

IF 6.8 2区医学 Q1 PHARMACOLOGY & PHARMACY

British Journal of Pharmacology Pub Date : 2024-06-13 DOI:10.1111/bph.16428

Yurong Zhang, Zengrong Chen, Junyan Guo, Qing Wan, Yingjie Zhang, Huihui Li, Haojie Rao, Jianfeng Yang, Pengfei Xu, Hong Chen, Miao Wang

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引用次数: 0

Abstract

Background and Purpose

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.

Experimental Approach

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.

Key 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.

Conclusion and Implications

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.

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因子 XII 和前胰激肽原促进小鼠微血管炎症和牛皮癣的发生。

背景和目的：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。因子 XII 的接触激活可启动血浆缓激肽-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：实验方法：在咪喹莫特诱导的银屑病小鼠模型中，研究了因子 XII 或其酶底物前激肽缺乏的影响。使用眼内共聚焦显微镜和激光多普勒血流计对皮肤微循环进行了评估。评估了阻断因子 XII 激活的新型抗体对银屑病预防的作用：主要结果：在人类和小鼠银屑病皮肤中，因子 XII 的表达明显上调。基因缺失因子 XII 或前allkikrein 可减轻咪喹莫特诱导的小鼠银屑病皮损。银屑病诱导增加了皮肤微血管的血液灌注，导致血管扩张、高渗透性和血管生成。它还促进了中性粒细胞与血管的相互作用、炎症细胞因子的释放，并增强了因子 XII / 前allkikrein 酶的活性，导致缓激肽升高。因子 XII 或前allkikrein 缺乏可改善这些微血管异常，并消除缓激肽增加。缓激肽 B2 受体拮抗剂再现了因子 XII / 前allkikrein 缺乏症对微血管的保护作用，减轻了银屑病皮损，并阻止了因子 XII / 前allkikrein 缺乏症对银屑病的保护作用。此外，用因子 XII 抗体治疗小鼠可减轻实验诱导的银屑病，并抑制微血管炎症：因子 XII 的活化通过前角蛋白依赖性缓激肽的形成促进了银屑病的发生，而缓激肽是银屑病微血管炎症的关键介质。抑制接触活化是治疗银屑病的一种新策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

British Journal of Pharmacology 医学-药学

CiteScore

15.40

自引率

12.30%

发文量

270

审稿时长

2.0 months

期刊介绍： The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.