Neutrophil activation by the tissue factor/Factor VIIa/PAR2 axis mediates fetal death in a mouse model of antiphospholipid syndrome
Patricia Redecha, … , Nigel Mackman, Guillermina Girardi
Patricia Redecha, … , Nigel Mackman, Guillermina Girardi
Published September 18, 2008
Citation Information: J Clin Invest. 2008;118(10):3453-3461. https://doi.org/10.1172/JCI36089.
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Research Article

Neutrophil activation by the tissue factor/Factor VIIa/PAR2 axis mediates fetal death in a mouse model of antiphospholipid syndrome

Abstract

Women with antiphospholipid syndrome (APS), a condition characterized by the presence of antiphospholipid antibodies (aPL), often suffer pregnancy-related complications, including miscarriage. We have previously shown that C5a induction of tissue factor (TF) expression in neutrophils contributes to respiratory burst, trophoblast injury, and pregnancy loss in mice treated with aPL. Here we analyzed how TF contributes to neutrophil activation and trophoblast injury in this model. Neutrophils from aPL-treated mice expressed protease-activated receptor 2 (PAR2), and stimulation of this receptor led to neutrophil activation, trophoblast injury, and fetal death. An antibody specific for human TF that has little impact on coagulation, but potently inhibits TF/Factor VIIa (FVIIa) signaling through PAR2, inhibited aPL-induced neutrophil activation in mice that expressed human TF. Genetic deletion of the TF cytoplasmic domain, which allows interaction between TF and PAR2, reduced aPL-induced neutrophil activation in aPL-treated mice. Par2–/– mice treated with aPL exhibited reduced neutrophil activation and normal pregnancies, which indicates that PAR2 plays an important role in the pathogenesis of aPL-induced fetal injury. We also demonstrated that simvastatin and pravastatin decreased TF and PAR2 expression on neutrophils and prevented pregnancy loss. Our results suggest that TF/FVIIa/PAR2 signaling mediates neutrophil activation and fetal death in APS and that statins may be a good treatment for women with aPL-induced pregnancy complications.

Authors

Patricia Redecha, Claus-Werner Franzke, Wolfram Ruf, Nigel Mackman, Guillermina Girardi

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Figure 1

PAR2 is required for aPL-IgG–induced neutrophil activity.

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PAR2 is required for aPL-IgG–induced neutrophil activity. (A) Immunohist...
(A) Immunohistochemical detection of TF and PAR2 on neutrophils from aPL-IgG– and NH-IgG–treated mice. Original magnification, ×400. (B) ROS production, measured as DHR-positive cells, on whole blood neutrophils from aPL-IgG–treated mice. The number of DHR-positive neutrophils increased in aPL-IgG–treated wild-type mice compared with untreated mice. ROS production in neutrophils did not increase in aPL-IgG–treated Par2–/– mice. (C and D) Phagocytic cells and DHR-positive cells in wild-type and Par2–/– mice. The percentage of phagocytic (C) and DHR-positive (D) neutrophils increased in aPL-IgG–treated wild-type mice compared with NH-IgG–treated mice. The absence of PAR2 prevented aPL-IgG–induced ROS production and phagocytosis. Incubation of neutrophils from Par2–/– mice with PMA induced increased ROS generation and phagocytosis, which indicates that the capacity of Par2–/– mice to generate oxidants or in phagocytosis is normal. (E and F) ROS production and phagocytosis in neutrophils from aPL-IgG–treated mice. (E) Neutrophils from Par1–/– mice treated with aPL-IgG showed increased ROS generation (E) as well as phagocytosis similar to aPL-IgG–treated wild-type mice (F). Increased ROS production was also observed in neutrophils from mice treated with hirudin or FPX in addition to aPL-IgG. n = 5–7 per group. *P < 0.05 versus NH-IgG; #P < 0.05 versus wild type. Data in C–F are mean ± SD.