Document Type

Article

Publication Date

1-29-2018

Abstract

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 αMβ2 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.

Keywords

cell biology, inflammation

Publication Title

Journal of Clinical Investigation

Volume

128

Issue

3

First Page

944

Last Page

959

Grant

HL052779-18; HL112666-2; HL126645-2; AI130131-1; Hemostasis and Thrombosis Research Society Mentored Research Award; AHA Scientist Development Award; Oscar D. Ratnoff Endowed Professorship; Shared Instrumentation Grant 1S10RR031845; SFB877 TP A11; ERC-StG-2012-311575_F-12

Funder

National Heart, Lung, and Blood Institute, National Institutes of Health (NIH); Baxalta Inc., Healthcare Corp.; American Heart Association; Young Scientist Foundation; National Center for Research Resources (NCRR), National Institutes of Health (NIH); German Research Society; European Research Council

Rights

© 2018, American Society for Clinical Investigation

Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.