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A role for uric acid and the nalp3 inflammasome in antiphospholipid antibody-induced IL-1β production by human first trimester trophoblast
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Mulla, Melissa J., Salmon, Jane E., Chamley, Larry W., Brosens, Jan J., Boeras, Crina M., Kavathas, Paula B. and Abrahams, Vikki M. (2013) A role for uric acid and the nalp3 inflammasome in antiphospholipid antibody-induced IL-1β production by human first trimester trophoblast. PLoS One, Volume 8 (Number 6). Article number e65237. doi:10.1371/journal.pone.0065237 ISSN 1932-6203.
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Official URL: http://dx.doi.org/10.1371/journal.pone.0065237
Abstract
Women with antiphospholipid syndrome (APS) are at risk of recurrent pregnancy loss and obstetrical disorders, such as preeclampsia and intrauterine growth restriction (IUGR). Antiphospholipid antibodies (aPL) directly target the placenta by binding beta(2)-glycoprotein I (beta(2)GPI) expressed on the trophoblast. We recently demonstrated in human first trimester trophoblast cells that anti-beta(2)GPI antibodies (Abs) induce the secretion of IL-1 beta in a Toll-like receptor 4 (TLR4)-dependent manner. IL-1 beta secretion requires processing of pro-IL-1 beta and this is mediated by the inflammasome, a complex of Nalp3, apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1. The objective of this study was to determine if aPL induce IL-1 beta production in trophoblast via the inflammasome. Using a human first trimester trophoblast cell line, we demonstrated that a mouse anti-beta(2)GPI mAb and human polyclonal aPL-IgG induce IL-1 beta processing and secretion, which was partially blocked upon caspase-1 inhibition. Nalp3 and ASC knockdown also attenuated anti-beta(2)GPI Ab-induced IL-1 beta secretion. Furthermore, aPL stimulated the production of uric acid in a TLR4-dependent manner; and inhibition of uric acid prevented aPL-induced IL-1 beta production by the trophoblast. These findings demonstrate that aPL, via TLR4 activation, induce a uric acid response in human trophoblast, which in turn activates the Nalp3/ASC inflammasome leading to IL-1 beta processing and secretion. This novel mechanism may account for the inflammation at the maternal-fetal interface, which causes placental dysfunction and increases the risk of adverse pregnancy outcome in patients with APS.
| Item Type: | Journal Article | ||||||||
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| Subjects: | R Medicine > RG Gynecology and obstetrics | ||||||||
| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Reproductive Health ( - until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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| Library of Congress Subject Headings (LCSH): | Antiphospholipid syndrome, Pregnancy -- Trimester, First, Trophoblast | ||||||||
| Journal or Publication Title: | PLoS One | ||||||||
| Publisher: | Public Library of Science | ||||||||
| ISSN: | 1932-6203 | ||||||||
| Official Date: | 6 June 2013 | ||||||||
| Dates: |
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| Volume: | Volume 8 | ||||||||
| Number: | Number 6 | ||||||||
| Article Number: | Article number e65237 | ||||||||
| DOI: | 10.1371/journal.pone.0065237 | ||||||||
| Status: | Peer Reviewed | ||||||||
| Publication Status: | Published | ||||||||
| Access rights to Published version: | Open Access (Creative Commons) | ||||||||
| Date of first compliant deposit: | 26 December 2015 | ||||||||
| Date of first compliant Open Access: | 26 December 2015 | ||||||||
| Funder: | American Heart Association (AHA), March of Dimes Birth Defects Foundation, National Institutes of Health (U.S.) (NIH) | ||||||||
| Grant number: | RO1AR49772 (NIH), RO1CA048511 (NIH) |
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