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A single-domain antibody targeting factor XII inhibits both thrombosis and inflammation.
Xu, Pengfei; Zhang, Yingjie; Guo, Junyan; Li, Huihui; Konrath, Sandra; Zhou, Peng; Cai, Liming; Rao, Haojie; Chen, Hong; Lin, Jian; Cui, Zhao; Ji, Bingyang; Wang, Jianwei; Li, Nailin; Liu, De-Pei; Renné, Thomas; Wang, Miao.
Afiliación
  • Xu P; 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.
  • Zhang Y; 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.
  • Guo J; 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.
  • Li H; College of Life Science, Zhejiang Normal University, Jinhua, Zhejiang, China.
  • Konrath S; 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.
  • Zhou P; Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
  • Cai L; Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
  • Rao H; Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • Chen H; 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.
  • Lin J; 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.
  • Cui Z; Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
  • Ji B; Renal Division, Peking University First Hospital, Beijing, China.
  • Wang J; Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • Li N; MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • Liu DP; Department of Medicine-Solna, Cardiovascular Medicine Unit, Karolinska Institute, Stockholm, Sweden.
  • Renné T; Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • Wang M; Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
Nat Commun ; 15(1): 7898, 2024 Sep 12.
Article en En | MEDLINE | ID: mdl-39266545
ABSTRACT
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trombosis / Factor XII / Ratones Noqueados / Anticuerpos de Dominio Único / Inflamación / Neutrófilos Límite: Animals / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trombosis / Factor XII / Ratones Noqueados / Anticuerpos de Dominio Único / Inflamación / Neutrófilos Límite: Animals / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido