Expression of the complement system's activation factors in plasma of patients with early/late‐onset severe pre‐eclampsia

He, Yanyan; Xu, Boming; Song, Di; Yu, Feng; Chen, Qian; Zhao, Ming‐Hui

doi:10.1111/aji.12541

Cited by 37 publications

(56 citation statements)

References 25 publications

(30 reference statements)

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“…NLRP3 inflammasome activation requires an already exaggerated inflammatory setting, as a priming signal is needed to achieve sufficient intracellular levels of NLRP3 and pro-IL-1b [15,54]. The choice of priming signal in the placenta was based on reports of elevated C5a and TNF-a in pre-eclampsia [28,32,[35][36][37][38][55][56][57], and supported by our discovery of C5a and TCC in the syncytium of pre-eclamptic placentas. The functional response confirms that C5a and TNF-a may serve as endogenous priming factors potentiating placental NLRP3 inflammasome activation.…”

Section: Discussionmentioning

confidence: 99%

“…Trophoblast NLRP3 activation has been assigned a role in pre-eclampsia development [31][32][33][34]. Raised serum and placental levels of IL-1b and excessive complement activation in women with pre-eclampsia [3,28,31,[35][36][37][38][39] further indicates a role for placental NLRP3 inflammasome involvement in this disease, but a detailed mechanistic outline with defined cellular involvement is missing. We hypothesize that complement-primed crystal-mediated activation of the NLRP3 inflammasome in trophoblasts leads to exaggerated IL-1b production and contributes to placental inflammation in pre-eclampsia.…”

Section: Introductionmentioning

confidence: 99%

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Placental inflammation in pre-eclampsia by Nod-like receptor protein (NLRP)3 inflammasome activation in trophoblasts

Stødle

Silva

Tangerås

et al. 2018

Clinical and Experimental Immunology

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Pre-eclampsia is associated with increased levels of cholesterol and uric acid and an inflamed placenta expressing danger-sensing pattern recognition receptors (PRRs). Crystalline cholesterol and uric acid activate the PRR Nod-like receptor protein (NLRP)3 inflammasome to release interleukin (IL)-1β and result in vigorous inflammation. We aimed to characterize crystal-induced NLRP3 activation in placental inflammation and examine its role in pre-eclampsia. We confirmed that serum total cholesterol and uric acid were elevated in pre-eclamptic compared to healthy pregnancies and correlated positively to high sensitivity C-reactive protein (hsCRP) and the pre-eclampsia marker soluble fms-like tyrosine kinase-1 (sFlt-1). The NLRP3 inflammasome pathway components (NLRP3, caspase-1, IL-1β) and priming factors [complement component 5a (C5a) and terminal complement complex (TCC)] were co-expressed by the syncytiotrophoblast layer which covers the placental surface and interacts with maternal blood. The expression of IL-1β and TCC was increased significantly and C5a-positive regions in the syncytiotrophoblast layer appeared more frequent in pre-eclamptic compared to normal pregnancies. In-vitro activation of placental explants and trophoblasts confirmed NLRP3 inflammasome pathway functionality by complement-primed crystal-induced release of IL-1β. This study confirms crystal-induced NLRP3 inflammasome activation located at the syncytiotrophoblast layer as a mechanism of placental inflammation and suggests contribution of enhanced NLRP3 activation to the harmful placental inflammation in pre-eclampsia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Placental inflammation in pre-eclampsia by Nod-like receptor protein (NLRP)3 inflammasome activation in trophoblasts

Stødle

Silva

Tangerås

et al. 2018

Clinical and Experimental Immunology

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“…C1q is the core molecule in the classical pathway of complement activation and is widely distributed in the human decidual stroma. [17][18][19][20][21][22][23] Therefore, establishing a normal range of complement components during pregnancy is important for clinical evaluation and research. [8][9][10] Complement factor B (CFB) can bind to C3b to form C3 convertase, promoting activation of the complement system via the alternative pathway, and this process can be inhibited by complement factor H (CFH), an inhibitor of the alternative pathway.…”

Section: Introductionmentioning

confidence: 99%

“…11,12 In general, moderate activation of the complement system is crucial for maintaining pregnancy, and any deviation from normal activation and regulation of the complement system may result in adverse pregnancy outcomes, such as recurrent spontaneous abortion, 13 preterm birth, [14][15][16] and preeclampsia. [17][18][19][20][21][22][23] Therefore, establishing a normal range of complement components during pregnancy is important for clinical evaluation and research. In addition, changes in circulating complement components may provide accessible biomarkers for predicting adverse pregnancy outcomes if "normal" pregnancy components are understood.…”

Section: Introductionmentioning

confidence: 99%

Normal range of complement components during pregnancy: A prospective study

Song

et al. 2019

American J Rep Immunol

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Problem The complement system plays a key role in normal placentation, and delicate regulation of complement system activation is critical for successful pregnancy. Therefore, establishing a normal range of complement components during pregnancy is important for clinical evaluation and research. Methods We performed a prospective study to investigate the normal range of complement components in circulation during different stages of pregnancy. Plasma concentrations of complement factor B (CFB), C1q, complement factor H (CFH), C3, C3c, and C4 were measured using an immunoturbidimetric assay; mannan‐binding lectin (MBL), C3a, C5a, and soluble C5b‐9 (sC5b‐9) levels at different time points of pregnancy were determined by enzyme‐linked immunosorbent assay (ELISA). Results A total of 733 plasma samples were collected from 362 women with a normal pregnancy and 65 samples from non‐pregnant women. In the first trimester of pregnancy, the levels of CFB, CFH, MBL, C3c, C4, and C3a were 414.5 ± 85.9 mg/L (95% CI for mean: 402.4‐426.6 mg/L), 381.0 ± 89.0 mg/L (95% CI for mean: 368.5‐393.6 mg/L), 4274.5 ± 2752 ng/mL (95% CI for mean: 3881.1‐4656.4 ng/mL), 1346.9 ± 419.8 mg/L (95% CI for mean: 1287.7‐1406.0 mg/L), 357.4 ± 101.8 mg/L (95% CI for mean: 343.0‐371.7 mg/L), and 182.5 ± 150.0 ng/mL (95% CI for mean: 186.9‐229.1 ng/mL), respectively. The levels of C3 and C4 increased gradually throughout pregnancy. The levels of C1q, C5a, and sC5b‐9 in the first and second trimesters were nearly the same as those in non‐pregnant women. Conclusion The results of this study show that pregnancy itself may influence the plasma levels of complement system components.

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“…Antiangiogenic soluble VEGFR1 (sFlt-1), antagonizes the proangiogenic ligands, VEGF and PlGF. In PE, the placenta is thought to abnormally release antiangiogenic factors, with a notable early-to-midgestation imbalance of circulating proangiogenic and antiangiogenic VEGF proteins in women in whom PE subsequently develops (8,13,(21)(22)(23)(24)(25)(26)(27). Increased circulating levels of sFlt-1 and decreased VEGF and PlGF have been consistently observed in PE and an elevated sFlt-1:PlGF ratio can predict PE before the appearance of clinical symptoms (8,25).…”

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confidence: 99%

Angiogenic factor imbalance precedes complement deposition in placentae of the BPH/5 model of preeclampsia

et al. 2018

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Preeclampsia (PE), a hypertensive disorder of pregnancy, is a leading cause of maternal and fetal morbidity and mortality. Although the etiology is unknown, PE is thought to be caused by defective implantation and decidualization in pregnancy. Pregnant blood pressure high (BPH)/5 mice spontaneously develop placentopathies and maternal features of human PE. We hypothesized that BPH/5 implantation sites have transcriptomic alterations. Next-generation RNA sequencing of implantation sites at peak decidualization, embryonic day (E)7.5, revealed complement gene up-regulation in BPH/5 vs. controls. In BPH/5, expression of complement factor 3 was increased around the decidual vasculature of E7.5 implantation sites and in the trophoblast giant cell layer of E10.5 placentae. Altered expression of VEGF pathway genes in E5.5 BPH/5 implantation sites preceded complement dysregulation, which correlated with abnormal vasculature and increased placental growth factor mRNA and VEGF expression at E7.5. By E10.5, proangiogenic genes were down-regulated, whereas antiangiogenic sFlt-1 was up-regulated in BPH/5 placentae. We found that early local misexpression of VEGF genes and abnormal decidual vasculature preceded sFlt-1 overexpression and increased complement deposition in BPH/5 placentae. Our findings suggest that abnormal decidual angiogenesis precedes complement activation, which in turn contributes to the aberrant trophoblast invasion and poor placentation that underlie PE.-Sones, J. L., Merriam, A. A., Seffens, A., Brown-Grant, D.-A., Butler, S. D., Zhao, A. M., Xu, X., Shawber, C. J., Grenier, J. K., Douglas, N. C. Angiogenic factor imbalance precedes complement deposition in placentae of the BPH/5 model of preeclampsia.

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Expression of the complement system's activation factors in plasma of patients with early/late‐onset severe pre‐eclampsia

Cited by 37 publications

References 25 publications

Placental inflammation in pre-eclampsia by Nod-like receptor protein (NLRP)3 inflammasome activation in trophoblasts

Placental inflammation in pre-eclampsia by Nod-like receptor protein (NLRP)3 inflammasome activation in trophoblasts

Normal range of complement components during pregnancy: A prospective study

Angiogenic factor imbalance precedes complement deposition in placentae of the BPH/5 model of preeclampsia

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