A single-domain antibody targeting factor XII inhibits both thrombosis and inflammation
Factor XII (FXII) is the zymogen of the plasma protease FXIIa that activates the intrinsic coagulation pathway and the kallikrein kinin-system. The role of FXII in inflammation has been obscure. Here, we report a single-domain antibody (nanobody, Nb) fused to the Fc region of a human immunoglobulin (Nb-Fc) that recognizes FXII in a conformation-dependent manner and interferes with FXIIa formation. Nb-Fc treatment inhibited arterial thrombosis in male mice without affecting hemostasis. In a mouse model of extracorporeal membrane oxygenation (ECMO), FXII inhibition or knockout reduced thrombus deposition on oxygenator membranes and systemic microvascular thrombi. ECMO increased circulating levels of D-dimer, alkaline phosphatase, creatinine and TNF-α and triggered microvascular neutrophil adherence, platelet aggregation and their interaction, which were substantially attenuated by FXII blockade. Both Nb-Fc treatment and FXII knockout markedly ameliorated immune complex-induced local vasculitis and anti-neutrophil cytoplasmic antibody-induced systemic vasculitis, consistent with selectively suppressed neutrophil migration. In human blood microfluidic analysis, Nb-Fc treatment prevented collagen-induced fibrin deposition and neutrophil adhesion/activation. Thus, FXII is an important mediator of inflammatory responses in vasculitis and ECMO, and Nb-Fc provides a promising approach to alleviate thrombo-inflammatory disorders.
Authors
- Liming Cai (ORCID: https://orcid.org/0000-0003-3445-3465)
- Pengfei Xu (ORCID: https://orcid.org/0009-0000-7624-4587)
- Thomas Renné (ORCID: https://orcid.org/0000-0003-4594-5975)
- Sandra Konrath (ORCID: https://orcid.org/0009-0007-2336-8982)
- Junyan Guo (ORCID: https://orcid.org/0000-0003-1400-948X)
- Nailin Li (ORCID: https://orcid.org/0000-0002-3848-7251)
- Bingyang Ji (ORCID: https://orcid.org/0000-0002-1410-6901)
- De‐Pei Liu (ORCID: https://orcid.org/0000-0002-2636-4297)
- Haojie Rao (ORCID: https://orcid.org/0009-0006-9156-2480)
- Zhao Cui (ORCID: https://orcid.org/0000-0002-5837-1926)
- Peng Zhou (ORCID: https://orcid.org/0000-0002-1436-9939)
- Huihui Li (ORCID: https://orcid.org/0000-0003-4608-1179)
- Miao Wang (ORCID: https://orcid.org/0000-0002-0532-6312)
- Hong Chen (ORCID: https://orcid.org/0000-0003-0356-2255)
- Jianwei Wang (ORCID: https://orcid.org/0000-0002-1116-4559)
- Jian Lin
- Yingjie Zhang (ORCID: https://orcid.org/0009-0003-3796-4444)
Institutions
- Zhejiang Normal University (CN)
- Royal College of Surgeons in Ireland (IE)
- Universität Hamburg (DE)
- Johannes Gutenberg University Mainz (DE)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Peking University (CN)
- Karolinska Institutet (SE)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- Beijing National Laboratory for Molecular Sciences (CN)
- Peking University First Hospital (CN)
- Zhengzhou Central Hospital (CN)
- Fu Wai Hospital (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-12
- DOI
- https://doi.org/10.1038/s41467-024-51745-4
- Citations
- 17
- Primary Topic
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Type
- article
- Field-Weighted Citation Impact
- 7.45
Funders
- Deutsche Forschungsgemeinschaft
- National Natural Science Foundation of China
- Zhejiang Normal University
- Chinese Academy of Medical Sciences
- National Key Research and Development Program of China