Preeclampsia & immune cell regulation | Assay Genie

According to the World Health Organization (WHO), one in ten pregnant women is affected by hypertensive disorders, and preeclampsia alone accounts for one in seven maternal deaths (1). Preeclampsia is defined as a hypertensive disorder that can complicate pregnancy after 20 weeks of gestation although it is debatable whether critical pro-inflammatory and oxidative stress responses are triggered in certain individuals nearly after conception. If the condition is progressive or left unattended, it can be further complicated by neurological dysregulations, a condition known as eclampsia.

Preeclampsia can be classified as mild or severe depending on the degree of hypertension, proteinuria, maternal organ dysfunction and the impact on intrauterine fetal development (2). To date, the only efficient therapeutic approach is preterm delivery of the fetus and placenta, which might result in serious complications of prematurity for the newborn baby. In fact, worldwide, preeclampsia is responsible for up to 20% of the 13 million preterm births each year, resulting in low birth-weight babies at increased risk for long term disabilities (3).

While the early pathogenesis of preeclampsia remains poorly characterized, it is understood that a diverse range of factors released by the placenta provokes latent oxidative stress, vascular endothelial complications, and inflammation which are culminated in the emergence of the symptoms of this disease. There is conflicting evidence suggesting the time of the initiation of such events over the course of pregnancy although elevated placental oxidative stress is already accelerated in preeclampsia as early as ~8–10 weeks’ gestation (4). The human placenta profoundly consists of a single multinucleated cell, the syncytiotrophoblast, which extrudes a large extent of extracellular vesicles (EVs) into the maternal blood. Placental EVs include macro-vesicles as well as smaller micro- and nano-vesicles, including exosomes (5). These EVs, especially the smaller micro- and nanovesicles, are present in the maternal circulation from as early as six weeks of gestation and in vitro experiments have reported that they can interact with endothelial cells, monocytes, lymphocytes, neutrophils, and platelets (6). What is more to the story is that if the vascular endothelium of the placenta is compromised it may lead to the vesiculation and shedding of endothelial and platelet microparticles (MPs) (7). Both types of MPs are described to promote inflammation and oxidative injuries in sterile conditions including acute coronary syndromes, ischemic stroke, diabetes or hypertensive pregnancy disorders (8-9).

According to the endosymbiotic theory, the evolutionary emergence of mitochondria is a result of the endocytosis of alpha-proteobacteria. Phylogenetic investigations support this assumption and on the other hand, there are several characteristic features which refer to prokaryotic ancestors. Indeed, the barrel-shaped mitochondrion with a diameter of 0.5 to 1.0 µm is bacterium-like. It has its own independent set of double-stranded mitochondrial DNA (mtDNA), which is uniquely not linear, but circular in form and it contains a large number of unmethylated CpG oligodeoxynucleotide motifs which are prevalent in bacterial but not vertebrate genomic DNAs (10).

Recently, in view of their endosymbiotic origin, the mitochondrion has come into focus as a major source of danger-associated molecular pattern (DAMP) in various sterile inflammatory conditions (11). mtDNA was proven to be highly potent immunomodulator facilitating dysfunctional inflammation and/or vascular dysfunction in preeclampsia, through Toll-like receptor 9 (TLR9) activation (12). The driving force of mtDNA as a DAMP in preeclampsia was further confirmed in a more recent work of Tong and co-workers (13). These authors reported that a major DAMP carried by placental EVs is actually mtDNA which can activate endothelial TLR9 and further mitigate inflammatory processes. Platelet-TLR9 has been shown to respond to free radical-altered self-ligands (13). Nevertheless, there is little currently known about the contribution of platelet EVs to the pathomechanism in preeclampsia.

An intriguing aspect of platelet MPs is that these tiny transporters carry a diverse cargo and the composition highly determined by the platelet activation process (14). More interestingly, activated platelets obtained from transfusion units were recently reported to release extracellular free mitochondria or extracellular, MP-encapsulated mitochondria which, upon release, had direct interactions with human leukocytes and promoted the release of proinflammatory mediators (15). These authors described later that MP-mediated transfer of a broad repertoire of platelet components to neutrophils occurred in blood samples of healthy human donors and the cargo included a large number of extracellular mitochondria (16). The first observations of this unique phenomenon in preeclampsia are yet to be confirmed. Our research team has currently designed further studies involving human participants to untangle the possible connections between both tissue and circulating EVs of placental and platelet origin and leukocyte recruitment with special emphasis on the behavior of cell-free mitochondria and mtDAMPs as potential cargos in the pathogenesis of preeclampsia. If our hypothesis is correct, this novel way of cross-talk can open completely new horizons in biomarker research or identifying new therapeutical targets to moderate or prevent the symptoms of preeclampsia.

1.WHO Recommendations for Prevention and Treatment of Pre-Eclampsia and Eclampsia. (2014). Accessed September, 2019.

2.Larsen TG, Hackmon R, Geraghty DE, Hviid TVF. Fetal human leukocyte antigen-C and maternal killer-cell immunoglobulin-like receptors in cases of severe preeclampsia. Placenta. 75:27-33 (2019).

3.Preeclampsia Foundation. Health Information FAQs. Accessed September, 2019.

4.Bilodeau JF. Review: maternal and placental antioxidant response to preeclampsia - impact on vasoactive eicosanoids. Placenta. 35 Suppl:S32-8. (2014).

5.Tong M, Kleffmann T, Pradhan S, Johansson CL, DeSousa J, Stone PR, James JL, Chen Q, Chamley LW. Proteomic characterization of macro-, micro- and nano-extracellular vesicles derived from the same first trimester placenta: relevance for feto-maternal communication. Hum Reprod. 31:687-99. (2016).

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7.Salem M, Kamal S, El Sherbiny W, Abdel Aal AA. Flow cytometric assessment of endothelial and platelet microparticles in preeclampsia and their relation to disease severity and Doppler parameters. Hematology. 20(3):154-9. (2015).

8.Puddu P, Puddu GM, Cravero E, Muscari S, Muscari A. The involvement of circulating microparticles in inflammation, coagulation and cardiovascular diseases. Can J Cardiol. 26(4):140-5. (2010).

9.Kohli S, Ranjan S, Hoffmann J, Kashif M, Daniel EA, Al-Dabet MM, Bock F, Nazir S, Huebner H, Mertens PR, Fischer KD, Zenclussen AC, Offermanns S, Aharon A, Brenner B, Shahzad K, Ruebner M, Isermann B. Maternal extracellular vesicles and platelets promote preeclampsia via inflammasome activation in trophoblasts. Blood. 128(17):2153-2164. (2016).

10.Krieg AM. CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol. 20:709-60. (2002).

11.Grazioli S, Pugin J. Mitochondrial Damage-Associated Molecular Patterns: From Inflammatory Signaling to Human Diseases. Front Immunol. 9:832. eCollection 2018. Review.

12.Goulopoulou S, Matsumoto T, Bomfim GF, Webb RC. Toll-like receptor 9 activation: a novel mechanism linking placenta-derived mitochondrial DNA and vascular dysfunction in pre-eclampsia. Clin Sci (Lond). 123(7):429-35. (2012).

13.Tong M, Johansson C, Xiao F, Stone PR, James JL, Chen Q, Cree LM, Chamley LW. Antiphospholipid antibodies increase the levels of mitochondrial DNA in placental extracellular vesicles: Alarmin-g for preeclampsia. Sci Rep. 7(1):16556. (2017).

14.Kuravi SJ, Harrison P, Rainger GE, Nash GB. Ability of Platelet-Derived Extracellular Vesicles to Promote Neutrophil-Endothelial Cell Interactions. Inflammation. 42(1):290-305. (2019).

15.Boudreau LH, Duchez AC, Cloutier N, Soulet D, Martin N, Bollinger J, Paré A, Rousseau M, Naika GS, Lévesque T, Laflamme C, Marcoux G, Lambeau G, Farndale RW, Pouliot M, Hamzeh-Cognasse H, Cognasse F, Garraud O, Nigrovic PA, Guderley H, Lacroix S, Thibault L, Semple JW, Gelb MH, Boilard E. Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation. Blood. 124(14):2173-83. (2014).

16.Duchez AC, Boudreau LH, Naika GS, Bollinger J, Belleannée C, Cloutier N, Laffont B, Mendoza-Villarroel RE, Lévesque T, Rollet-Labelle E, Rousseau M, Allaeys I, Tremblay JJ, Poubelle PE, Lambeau G, Pouliot M, Provost P, Soulet D, Gelb MH, Boilard E. Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A2-IIA. Proc Natl Acad Sci U S A. 112(27):E3564-73. (2015).