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

Patricia Redecha, et al. 2008. J. Clin. Invest. 118, 3453-3461

Speaker: Chia-Chun Tsia (蔡佳純)                                         Time: 15:00~16:00, Nov. 19, 2008

Commentator: Dr. Chrong-Reen Wang (王崇任醫師)                    Place: Room 601

Abstract:

     Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the formation of diffused thrombosis. In pregnant women, in addition, APS causes severe pregnancy complications, such as miscarriage, premature birth, and fetal death. APS is resulted from complement C5a activation by antiphospholipid antibody (aPL) to induce tissue factor (TF) expression in neutrophils. TF/FVIIa complex is an initiator of blood coagulation and can elicit cellular signaling pathway via proteolytic activation of protease-activated receptor 2 (PAR2) to mediate inflammation (1). Here, the authors investigated the correlation between TF/FVIIa/PAR2 and neutrophil activation in aPL-treated mice. A specific anti-TF mAb blocking TF/FVIIa signaling through PAR2 reduced neutrophil activity. The reduction indicates TF/FVIIa/PAR2 signaling is required for aPL-IgG-induced increase of neutrophil activity. The mice with genetic deletion in TF cytoplasmic domain which is responsible for the signaling of TF/FVIIa-induced cellular responses, shows less neutrophil activity compared with wild-type mice. PAR2^-/- mice treated with aPL displayed decreased neutrophil activation and normal pregnancies, and these evidences show that PAR2 is essential for the pregnancy loss of aPL-treated mice. Previous studies have shown statins, compounds used to lower the level of cholesterol in blood, reduced TF expression and activity in blood monocytes in patients with nephritic syndrome (2). The authors proved that statins also decreased TF and PAR2 expression in neutrophils and prevented mice treated with aPL from pregnancy loss. The study suggests that TF/FVIIa/PAR2 axis regulates neutrophil activation and pregnancy loss in a mouse model of APS and provides a way for therapy in patients with APS. 

References:

1.      S. Strukova. 2006. Blood coagulation-dependent inflammation. Coagulation-dependent inflammation and inflammation-dependent thrombosis. Front. Biosci. 11, 59-80.

2.      Wei, J.L., Cui, H.M., and Ma, C.Y. 2007. Simvastatin inhibits tissue factor secretion by peripheral blood mononuclear cells in patients with primary nephrotic syndrome.                                

   Eur. J. Med. Res. 12, 216-221.