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.
College of Life Science, Zhejiang Normal University, Jinhua, Zhejiang, China.
Nat Commun. 2024 Sep 12;15(1):7898. doi: 10.1038/s41467-024-51745-4.
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.
凝血因子 XII（FXII）是血浆蛋白酶 FXIIa 的酶原，可激活内在凝血途径和激肽释放酶-缓激肽系统。FXII 在炎症中的作用一直不清楚。在这里，我们报告了一种单域抗体（纳米抗体，Nb）与人类免疫球蛋白的 Fc 区融合（Nb-Fc），它以构象依赖的方式识别 FXII 并干扰 FXIIa 的形成。Nb-Fc 治疗抑制了雄性小鼠的动脉血栓形成，而不影响止血。在体外膜肺氧合（ECMO）的小鼠模型中，FXII 抑制或敲除减少了氧合器膜上的血栓沉积和全身微血管血栓。ECMO 增加了循环中二聚体 D、碱性磷酸酶、肌酐和 TNF-α 的水平，并引发了微血管中性粒细胞黏附、血小板聚集及其相互作用，这些作用被 FXII 阻断显著减弱。Nb-Fc 治疗和 FXII 敲除都显著改善了免疫复合物诱导的局部血管炎和抗中性粒细胞胞质抗体诱导的全身血管炎，与选择性抑制中性粒细胞迁移一致。在人类血液微流体分析中，Nb-Fc 治疗可防止胶原诱导的纤维蛋白沉积和中性粒细胞黏附和/激活。因此，FXII 是血管炎和 ECMO 中炎症反应的重要介质，Nb-Fc 为减轻血栓炎症性疾病提供了一种有前途的方法。
