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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.sup.-/-]) 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 [S.sup.474] ([pAktS.sup.474]). Downstream of [pAkt2S.sup.474], FXII stimulation of neutrophils upregulated surface expression of [[alpha].sub.M][[beta].sub.2] 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.sup.-/-] 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.sup.-/-] hosts was sufficient to correct the neutrophil migration defect in [F12.sup.-/-] 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., Introduction Factor XII (FXII) is the zymogen of serine protease factor XIIa (FXIIa). Discovered by Ratnoff 60 years ago, FXII was first recognized as essential for surface-activated blood coagulation. FXII [...]