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 3

Par2–/– mice are protected from trophoblast oxidative injury and fetal death.

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Par2–/– mice are protected from trophoblast oxidative injury and fetal ...
Pregnant Par2–/– or wild-type mice were given 10 mg aPL-IgG or NH-IgG i.p. on days 8 and 12. (A) Mice were killed on day 15 of pregnancy, uteri were dissected, and FRF was calculated as described in Methods. In matings of wild-type mice, approximately 40% of the embryos of mice treated with aPL-IgG were resorbed; in contrast, Par2–/– mice showed a reduction in aPL-IgG–induced FRF. *P < 0.05 versus NH-IgG. n = 5–7 mice per group. Data are mean ± SD. (B and C) Mice were killed on day 8, 2 h after aPL-IgG or NH-IgG injection. Uteri were dissected, and decidua sections were cut and stained with an anti-C3 antibody (B) or DHE (C) to measure superoxide generation. (B) The chromogen was DAB (brown), and the counterstain was hematoxylin. In aPL-IgG–treated wild-type mice, there was extensive C3 staining (brown) in deciduae as well as embryo debris (ED). In contrast, the decidual tissue from aPL-IgG–treated Par2–/– mice showed minimal staining for C3 at the ectoplacental cone (ec) and intact embryo (E). (C) aPL-IgG–induced superoxide production in wild-type mice was attenuated in Par2–/– mice. Oxidative damage in deciduae from aPL-IgG–treated PAR2 mice was minimal and not different from that in NH-IgG–treated wild-type mice. Scale bars: 100 μm (B); 40 μm (C).