Tissue factor: a link between C5a and neutrophil activation in antiphospholipid antibody induced fetal injury.
Fetal loss in patients with antiphospholipid (aPL) antibodies has been ascribed to thrombosis of placental vessels. However, we have shown that inflammation, specifically activation of complement with generation of the anaphylotoxin C5a, is an essential trigger of fetal injury. In this study, we analyzed the role of the procoagulant molecule tissue factor (TF) in a mouse model of aPL antibody-induced pregnancy loss. We found that either blockade of TF with a monoclonal antibody in wild-type mice or a genetic reduction of TF prevented aPL antibody-induced inflammation and pregnancy loss. In response to aPL antibody-generated C5a, neutrophils express TF potentiating inflammation in the deciduas and leading to miscarriages. Importantly, we showed that TF in myeloid cells but not fetal-derived cells (trophoblasts) was associated with fetal injury, suggesting that the site for pathologic TF expression is neutrophils. We found that TF expression in neutrophils contributes to respiratory burst and subsequent trophoblast injury and pregnancy loss induced by aPL antibodies. The identification of TF as an important mediator of C5a-induced oxidative burst in neutrophils in aPL-induced fetal injury provides a new target for therapy to prevent pregnancy loss in the antiphospholipid syndrome.
Redecha
Patricia
P
Hospital for Special Surgery, Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.
Tilley
Rachel
R
Tencati
Michael
M
Salmon
Jane E
JE
Kirchhofer
Daniel
D
Mackman
Nigel
N
Girardi
Guillermina
G
D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000276:immunology*; D015936:Complement C5a / Q000378:metabolism*; D020964:Embryo Loss / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D018375:Neutrophil Activation / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D018384:Oxidative Stress; D011247:Pregnancy; D049188:Prenatal Injuries / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D044087:Receptor, Anaphylatoxin C5a / Q000378:metabolism; D015398:Signal Transduction; D013925:Thromboplastin / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D017152:Antibodies, Antiphospholipid; D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a; D013925:Thromboplastin