PAD4 Deficiency Decreases Inflammation and Susceptibility to Pregnancy Loss in a Mouse Model

Overview

Journal Biol Reprod

Publisher Oxford University Press

Specialty Reproductive Medicine

Date 2016 Dec 24

PMID 28007693

Citations 21

Authors

Luise Erpenbeck

Chanchal Sur Chowdhury

Zsuzsanna K Zsengeller

Maureen Gallant

Suzanne D Burke

Stephen Cifuni

Sinuhe Hahn

Denisa D Wagner

S Ananth Karumanchi

Affiliations

Soon will be listed here.

Abstract

Inflammation is thought to play a critical role in the pathogenesis of placentation disorders such as recurrent miscarriages, growth restriction, and preeclampsia. Recently, neutrophil extracellular traps (NETs) have emerged as a potential mechanism for promoting inflammation in both infectious and noninfectious disorders. To investigate a pathogenic role for NETs in placentation disorders, we studied a model of antiangiogenic factor-mediated pregnancy loss in wild-type (WT) mice and in mice deficient in peptidylarginine deiminase 4 (Padi4) that are unable to form NETs. Overexpression of soluble fms-like tyrosine kinase 1 (sFlt-1), an antiangiogenic protein that is pathogenically linked with abnormal placentation disorders during early gestation, resulted in pregnancy loss and large accumulation of neutrophils and NETs in WT placentas. Interestingly, sFlt-1 overexpression in Padi4 mice resulted in dramatically lower inflammatory and thrombotic response, which was accompanied by significant reduction in pregnancy losses. Inhibition of NETosis may serve as a novel target in disorders of impaired placentation.

Citing Articles

Neutrophil extracellular traps in homeostasis and disease.

Wang H, Kim S, Lei Y, Wang S, Wang H, Huang H Signal Transduct Target Ther. 2024; 9(1):235.

PMID: 39300084 PMC: 11415080. DOI: 10.1038/s41392-024-01933-x.

Bioinformatics identification and validation of maternal blood biomarkers and immune cell infiltration in preeclampsia: An observational study.

Wang H, Li H, Rong Y, He H, Wang Y, Cui Y Medicine (Baltimore). 2024; 103(21):e38260.

PMID: 38788026 PMC: 11124706. DOI: 10.1097/MD.0000000000038260.

Platelet-derived microparticles and their cargos: The past, present and future.

Guo J, Cui B, Zheng J, Yu C, Zheng X, Yi L Asian J Pharm Sci. 2024; 19(2):100907.

PMID: 38623487 PMC: 11016590. DOI: 10.1016/j.ajps.2024.100907.

Platelet factor 4 limits neutrophil extracellular trap- and cell-free DNA-induced thrombogenicity and endothelial injury.

Ngo A, Skidmore A, Oberg J, Yarovoi I, Sarkar A, Levine N JCI Insight. 2023; 8(22).

PMID: 37991024 PMC: 10721321. DOI: 10.1172/jci.insight.171054.

Exosomal miR-146a-5p derived from human umbilical cord mesenchymal stem cells can alleviate antiphospholipid antibody-induced trophoblast injury and placental dysfunction by regulating the TRAF6/NF-κB axis.

Lv Q, Wang Y, Tian W, Liu Y, Gu M, Jiang X J Nanobiotechnology. 2023; 21(1):419.

PMID: 37957714 PMC: 10641965. DOI: 10.1186/s12951-023-02179-5.

References

Wang Y, Gu Y, Philibert L, Lucas M . Neutrophil activation induced by placental factors in normal and pre-eclamptic pregnancies in vitro. Placenta. 2001; 22(6):560-5. DOI: 10.1053/plac.2001.0691. View

Yalavarthi S, Gould T, Rao A, Mazza L, Morris A, Nunez-Alvarez C . Release of neutrophil extracellular traps by neutrophils stimulated with antiphospholipid antibodies: a newly identified mechanism of thrombosis in the antiphospholipid syndrome. Arthritis Rheumatol. 2015; 67(11):2990-3003. PMC: 4626310. DOI: 10.1002/art.39247. View

Kan R, Jin M, Subramanian V, Causey C, Thompson P, Coonrod S . Potential role for PADI-mediated histone citrullination in preimplantation development. BMC Dev Biol. 2012; 12:19. PMC: 3430579. DOI: 10.1186/1471-213X-12-19. View

Lewis H, Liddle J, Coote J, Atkinson S, Barker M, Bax B . Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation. Nat Chem Biol. 2015; 11(3):189-91. PMC: 4397581. DOI: 10.1038/nchembio.1735. View

Chen G, Zhang D, Fuchs T, Manwani D, Wagner D, Frenette P . Heme-induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease. Blood. 2014; 123(24):3818-27. PMC: 4055928. DOI: 10.1182/blood-2013-10-529982. View

Redman C, Sargent I . Immunology of pre-eclampsia. Am J Reprod Immunol. 2010; 63(6):534-43. DOI: 10.1111/j.1600-0897.2010.00831.x. View

Farrera C, Fadeel B . Macrophage clearance of neutrophil extracellular traps is a silent process. J Immunol. 2013; 191(5):2647-56. DOI: 10.4049/jimmunol.1300436. View

Metzler K, Fuchs T, Nauseef W, Reumaux D, Roesler J, Schulze I . Myeloperoxidase is required for neutrophil extracellular trap formation: implications for innate immunity. Blood. 2010; 117(3):953-9. PMC: 3035083. DOI: 10.1182/blood-2010-06-290171. View

Friggeri A, Banerjee S, Xie N, Cui H, de Freitas A, Zerfaoui M . Extracellular histones inhibit efferocytosis. Mol Med. 2012; 18:825-33. PMC: 3409281. DOI: 10.2119/molmed.2012.00005. View

10.

Brill A, Fuchs T, Savchenko A, Thomas G, Martinod K, De Meyer S . Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost. 2011; 10(1):136-44. PMC: 3319651. DOI: 10.1111/j.1538-7836.2011.04544.x. View

11.

Maynard S, Min J, Merchan J, Lim K, Li J, Mondal S . Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003; 111(5):649-58. PMC: 151901. DOI: 10.1172/JCI17189. View

12.

Wang Y, Wysocka J, Sayegh J, Lee Y, Perlin J, Leonelli L . Human PAD4 regulates histone arginine methylation levels via demethylimination. Science. 2004; 306(5694):279-83. DOI: 10.1126/science.1101400. View

13.

Lim M, Kuiper J, Katchky A, Goldberg H, Glogauer M . Rac2 is required for the formation of neutrophil extracellular traps. J Leukoc Biol. 2011; 90(4):771-6. DOI: 10.1189/jlb.1010549. View

14.

Zhong X, Laivuori H, Livingston J, Ylikorkala O, Sibai B, Holzgreve W . Elevation of both maternal and fetal extracellular circulating deoxyribonucleic acid concentrations in the plasma of pregnant women with preeclampsia. Am J Obstet Gynecol. 2001; 184(3):414-9. DOI: 10.1067/mob.2001.109594. View

15.

Rajakumar A, Cerdeira A, Rana S, Zsengeller Z, Edmunds L, Jeyabalan A . Transcriptionally active syncytial aggregates in the maternal circulation may contribute to circulating soluble fms-like tyrosine kinase 1 in preeclampsia. Hypertension. 2012; 59(2):256-64. PMC: 3319764. DOI: 10.1161/HYPERTENSIONAHA.111.182170. View

16.

Marder W, Knight J, Kaplan M, Somers E, Zhang X, ODell A . Placental histology and neutrophil extracellular traps in lupus and pre-eclampsia pregnancies. Lupus Sci Med. 2016; 3(1):e000134. PMC: 4854113. DOI: 10.1136/lupus-2015-000134. View

17.

Fuchs T, Bhandari A, Wagner D . Histones induce rapid and profound thrombocytopenia in mice. Blood. 2011; 118(13):3708-14. PMC: 3186342. DOI: 10.1182/blood-2011-01-332676. View

18.

Savchenko A, Borissoff J, Martinod K, De Meyer S, Gallant M, Erpenbeck L . VWF-mediated leukocyte recruitment with chromatin decondensation by PAD4 increases myocardial ischemia/reperfusion injury in mice. Blood. 2013; 123(1):141-8. PMC: 3879903. DOI: 10.1182/blood-2013-07-514992. View

19.

Gupta A, Hasler P, Holzgreve W, Hahn S . Neutrophil NETs: a novel contributor to preeclampsia-associated placental hypoxia?. Semin Immunopathol. 2007; 29(2):163-7. DOI: 10.1007/s00281-007-0073-4. View

20.

Hodson M . Clinical studies of rhDNase in moderately and severely affected patients with cystic fibrosis--an overview. Respiration. 1995; 62 Suppl 1:29-32. DOI: 10.1159/000196491. View