2. Academic Validation
  3. Factor XII and prekallikrein promote microvascular inflammation and psoriasis in mice

Factor XII and prekallikrein promote microvascular inflammation and psoriasis in mice

  • Br J Pharmacol. 2024 Jun 13. doi: 10.1111/bph.16428.
Yurong Zhang 1,  Zengrong Chen 1,  Junyan Guo 1 2,  Qing Wan 1,  Yingjie Zhang 1,  Huihui Li 1,  Haojie Rao 1,  Jianfeng Yang 1,  Pengfei Xu 1,  Hong Chen 1,  Miao Wang 1 3 4
Affiliations

Affiliations

  • 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.
PMID: 38872396 DOI: 10.1111/bph.16428
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.

Keywords

bradykinin; factor XII; inflammation; microcirculation; prekallikrein; psoriasis.

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