Factor XII and uPAR upregulate neutrophil functions to influence wound healing

TY - JOUR

T1 - Factor XII and uPAR upregulate neutrophil functions to influence wound healing

AU - Stavrou, Evi X

AU - Fang, Chao

AU - Bane, Kara L

AU - Long, Andy T

AU - Naudin, Clément

AU - Kucukal, Erdem

AU - Gandhi, Agharnan

AU - Brett-Morris, Adina

AU - Mumaw, Michele M

AU - Izadmehr, Sudeh

AU - Merkulova, Alona

AU - Reynolds, Cindy C

AU - Alhalabi, Omar

AU - Nayak, Lalitha

AU - Yu, Wen-Mei

AU - Qu, Cheng-Kui

AU - Meyerson, Howard J

AU - Dubyak, George R

AU - Gurkan, Umut A

AU - Nieman, Marvin T

AU - Sen Gupta, Anirban

AU - Renné, Thomas

AU - Schmaier, Alvin H

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1172/JCI92880

DO - 10.1172/JCI92880

M3 - SCORING: Journal article

C2 - 29376892

VL - 128

SP - 944

EP - 959

JO - J CLIN INVEST

JF - J CLIN INVEST

SN - 0021-9738

IS - 3

ER -