Antiphospholipid antibodies induce a pro-inflammatory response in first trimester trophoblast via the TLR4/MyD88 pathway.
OBJECTIVE
Women with antiphospholipid antibodies (aPL) are at risk for recurrent miscarriage, pre-eclampsia, and pre-term labor. aPL target the placenta directly by binding to beta(2)-glycoprotein I (beta(2)GPI) expressed on the surface of trophoblast cells. The objective of this study was to determine the effects of aPL on trophoblast function and the mechanisms involved.


METHODS
First trimester trophoblast cells were treated with anti-beta(2)GPI monoclonal antibodies and patient-derived aPL, after which cell survival and function was evaluated.


RESULTS
We report that anti-beta(2)GPI antibodies trigger an inflammatory response in trophoblast, characterized by increased secretion of interleukin (IL)-8, MCP-1, GRO-alpha, and IL-1beta, and that this occurs in a TLR-4/MyD88-dependent manner. At high concentrations, these antibodies also induce caspase-mediated cell death. This was attenuated upon disabling of the MyD88 pathway, suggesting that anti-beta(2)GPI-induced inflammatory mediators compromise trophoblast survival by acting in an autocrine/paracrine manner. Enhanced IL-8, GRO-alpha, and IL-1beta secretion also occurred when trophoblast cells were incubated with antibodies from patients with antiphospholipid syndrome. Heparin, which acts as a pro-survival factor in human trophoblast, attenuated the anti-beta(2)GPI antibody-mediated cell death, and also the pro-inflammatory response, but only at high concentrations.


CONCLUSIONS
These findings demonstrate that aPL triggers a placental inflammatory response via the TLR-4/MyD88 pathway, which in turn compromises trophoblast survival. Thus, the TLR-4/MyD88 pathway may provide a new therapeutic target to improve pregnancy outcome in antiphospholipid syndrome patients.
Mulla
Melissa J
MJ
Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510, USA.
Brosens
Jan J
JJ
Chamley
Larry W
LW
Giles
Ian
I
Pericleous
Charis
C
Rahman
Anisur
A
Joyce
Shawna K
SK
Panda
Britta
B
Paidas
Michael J
MJ
Abrahams
Vikki M
VM
D000328:Adult; D000368:Aged; D017152:Antibodies, Antiphospholipid / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology; D016736:Antiphospholipid Syndrome / Q000276:immunology; D017209:Apoptosis; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000378:metabolism; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006493:Heparin / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D008875:Middle Aged; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014327:Trophoblasts / Q000276:immunology*; D053482:beta 2-Glycoprotein I / Q000276:immunology
D017152:Antibodies, Antiphospholipid; D000911:Antibodies, Monoclonal; C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D016207:Cytokines; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D053482:beta 2-Glycoprotein I; D006493:Heparin