Coagulation factor XII (FXII) deficiency is associated with decreased neutrophil migration, but the mechanisms remain uncharacterized. Here, we examine how FXII contributes to the inflammatory response. In 2 models of sterile inflammation, FXII-deficient mice (F12^–/–) had fewer neutrophils recruited than WT mice. We discovered that neutrophils produced a pool of FXII that is functionally distinct from hepatic-derived FXII and contributes to neutrophil trafficking at sites of inflammation. FXII signals in neutrophils through urokinase plasminogen activator receptor–mediated (uPAR-mediated) Akt2 phosphorylation at S⁴⁷⁴ (pAktS⁴⁷⁴). Downstream of pAkt2S⁴⁷⁴, FXII stimulation of neutrophils upregulated surface expression of α_Mβ₂ integrin, increased intracellular calcium, and promoted extracellular DNA release. The sum of these activities contributed to neutrophil cell adhesion, migration, and release of neutrophil extracellular traps in a process called NETosis. Decreased neutrophil signaling in F12^–/– mice resulted in less inflammation and faster wound healing. Targeting hepatic F12 with siRNA did not affect neutrophil migration, whereas WT BM transplanted into F12^–/– hosts was sufficient to correct the neutrophil migration defect in F12^–/– mice and restore wound inflammation. Importantly, these activities were a zymogen FXII function and independent of FXIIa and contact activation, highlighting that FXII has a sophisticated role in vivo that has not been previously appreciated.

中文翻译：

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XII 因子和 uPAR 上调中性粒细胞功能，影响伤口愈合


凝血因子 XII (FXII) 缺乏与中性粒细胞迁移减少有关，但其机制仍不清楚。在这里，我们研究 FXII 如何促进炎症反应。在两种无菌炎症模型中，FXII 缺陷型小鼠 ( F12 ^–/– ) 招募的中性粒细胞比 WT 小鼠少。我们发现中性粒细胞产生了一组 FXII，其功能与肝源性 FXII 不同，并有助于炎症部位的中性粒细胞运输。 FXII 通过尿激酶纤溶酶原激活剂受体介导（uPAR 介导）S ⁴⁷⁴ (pAktS ⁴⁷⁴ ) 处的 Akt2 磷酸化在中性粒细胞中发出信号。 pAkt2S ⁴⁷⁴的下游，FXII 刺激中性粒细胞上调 α _M β ₂整合素的表面表达，增加细胞内钙，并促进细胞外 DNA 释放。这些活动的总和有助于中性粒细胞粘附、迁移和中性粒细胞胞外陷阱的释放，这一过程称为 NETosis。 F12 ^–/–小鼠中性粒细胞信号传导减少导致炎症减少和伤口愈合更快。用 siRNA 靶向肝脏F12不会影响中性粒细胞迁移，而移植到F12 ^–/–宿主中的 WT BM 足以纠正F12 ^–/–小鼠的中性粒细胞迁移缺陷并恢复伤口炎症。重要的是，这些活性是酶原 FXII 的功能，并且独立于 FXIIa 和接触激活，这突出表明 FXII 在体内具有以前未被认识到的复杂作用。