TLR9 (Toll-Like Receptor 9) Agonist Suppresses Angiogenesis by Differentially Regulating VEGFA (Vascular Endothelial Growth Factor A) and sFLT1 (Soluble Vascular Endothelial Growth Factor Receptor 1) in Preeclampsia

He, Biwei; Yang, Xingyu; Li, Yamei; Huang, Ding; Xu, Xin; Yang, Wenjun; Dai, Yan; Zhang, Huijuan; Chen, Zhengjun; Cheng, Weiwei

doi:10.1161/hypertensionaha.117.10510

Cited by 45 publications

(55 citation statements)

References 49 publications

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“…Cell-free circulating mtDNA (CFCmtDNA) can act as a damage-associated molecular pattern (DAMP) molecule, which elicits an immune response via activation of the pattern recognition receptor, Toll-like receptor-9 (TLR-9) 6 . We and others have previously reported that activation of TLR-9 during pregnancy induced preeclampsia-like signs in rats and mice 10, 11 . In line with these observations, TLR-9 activity was greater in pregnant women with preeclampsia as compared to healthy pregnant women 12 .…”

Section: Introductionmentioning

confidence: 74%

Concentrations and immunostimulatory potential of circulating cell-free membrane-bound and membrane-unbound mitochondrial DNA in preeclampsia

Cushen

Ricci

et al. 2021

Preprint

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Cell-free circulating mitochondrial DNA (CFCmtDNA) is a damage-associated molecular pattern (DAMP) that can activate Toll-like receptor 9 (TLR-9). The main objectives of this case-control study were 1) to determine absolute concentrations and immunostimulatory capacity of CFCmtDNA, in membrane-bound and -unbound states, in cases with preeclampsia and healthy controls and 2) to implement a bootstrapped penalized regression analysis to establish the contribution of CFCmtDNA to preeclampsia diagnosis and its interaction with commonly collected patient characteristics. To determine the contribution of membrane-bound and -unbound CFCmtDNA in preeclampsia, DNA from plasma samples was exctracted with lysis buffer (membrane-unbound) and without lysis buffer (membrane-bound). CFCmtDNA, quantified using absolute PCR quantification protocol, was reduced in preeclampsia compared to healthy controls (P≤0.02). While the pattern of reduced CFCmtDNA in preeclampsia was similar between methods of DNA extraction, DNA isolation with membrane lysis buffer resulted in 1,000-fold higher CFCmtDNA quantification in the preeclampsia group (P=0.0014) and 430-fold higher CFCmtDNA quantification in the control group (P<0.0001). Even though CFCmtDNA concentrations were reduced, plasma from women with preeclampsia induced greater TLR-9 activation than plasma from gestational age matched controls (P≤0.01) as monitored using SEAP reporter 293 cells expressing human TLR-9. Penalized regression analysis showed that women with preeclampsia are strongly likely to have high concentrations of nDNA and DNase I along with a prior history of preeclampsia. Low concentrations of CFCmtDNA and mode of delivery were also associated with preeclampsia. In conclusion, our data demonstrate increases in the immunostimulatory potential of CFCmtDNA and upregulation of DNA degradation mechanisms in women with preeclampsia at the third trimester.

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Section: Introductionmentioning

confidence: 74%

Concentrations and immunostimulatory potential of circulating cell-free membrane-bound and membrane-unbound mitochondrial DNA in preeclampsia

Cushen

Ricci

et al. 2021

Preprint

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“…Exciting new work by He et al . has identified an additional role for TLR9 in preeclampsia where they established that TLR9 supressed angiogenesis in part by increasing sFlt-1 expression in a murine model of preeclampsia 27 . Furthermore, research carried out in spontaneous hypertensive rats, illustrated circulating mtDNA may lead to the activation of the innate immune system through TLR9 21 .…”

Section: Discussionmentioning

confidence: 99%

Activation of a TLR9 mediated innate immune response in preeclampsia

Williamson

McCarthy

Kenny

et al. 2019

Sci Rep

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Preeclampsia is a multisystemic disorder leading to the development of a placental ischemic microenvironment with a resultant increase in oxidative stress. There is evidence that mitochondrial dysfunction and the innate immune system both play a role in the pathophysiology of this disease. Mitochondrial DAMPs such as mtDNA bind specific pattern recognition receptors such as Toll-like receptor 9 (TLR9) on the endosomal surface of immune cells, in particular neutrophils, subsequently activating them and triggering an innate response. We hypothesised that the exaggerated innate immune response seen in preeclampsia is provoked by dysfunctional mitochondria. Here we provide evidence that TLR9 activity is significantly increased at time of disease in women with preeclampsia. Furthermore, we show activation of neutrophil markers, Calprotectin, Myeloperoxidase (MPO), and IL-8 are significantly increased at time of disease compared to uncomplicated pregnancies. This research supports a potential role of TLR9 activation of an innate immune response evident in preeclampsia which may possibly be initially triggered by dysfunctional mitochondria.

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“…We recently showed that expression levels of TLR9 and the amount of cffDNA from the placenta were higher in PE patients compared with that in women with normal placenta (NP), and PE-derived cffDNA stimulated levels of inflammatory cytokine, including IL-1β and sEng secretion depend on TLR9 signaling, compared with NP-derived cffDNA (105). Moreover, a synthetic TLR9 ligand activated inflammatory responses including IL-6 secretion together with stimulation of sFlt1 secretion, while inhibition of TLR9 reduced sFlt1 secretion in human trophoblast cells (106). In mice, administration of a TLR9 ligand induces PE-like symptoms, such as hypertension, proteinuria, placental inflammation, and FGR.…”

Section: Extracellular Dna and The Nlrp3 Inflammasome In Pementioning

confidence: 98%

Role of the NLRP3 Inflammasome in Preeclampsia

2020

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Reproduction involves tightly regulated series of events and the immune system is involved in an array of reproductive processes. Disruption of well-controlled immune functions leads to infertility, placental inflammation, and numerous pregnancy complications, including preeclampsia (PE). Inflammasomes are involved in the process of pathogen clearance and sterile inflammation. They are large multi-protein complexes that are located in the cytosol and play key roles in the production of the pivotal inflammatory cytokines, interleukin (IL)-1β and IL-18, and pyroptosis. The nucleotide-binding oligomerization domain, leucine-rich repeat-, and pyrin domaincontaining 3 (NLRP3) inflammasome is a key mediator of sterile inflammation induced by various types of damage-associated molecular patterns (DAMPs). Recent evidence indicates that the NLRP3 inflammasome is involved in pregnancy dysfunction, including PE. Many DAMPs (uric acid, palmitic acid, high-mobility group box 1, advanced glycation end products, extracellular vesicles, cell-free DNA, and free fatty acids) are increased and associated with pregnancy complications, especially PE. This review focuses on the role of the NLRP3 inflammasome in the pathophysiology of PE.

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TLR9 (Toll-Like Receptor 9) Agonist Suppresses Angiogenesis by Differentially Regulating VEGFA (Vascular Endothelial Growth Factor A) and sFLT1 (Soluble Vascular Endothelial Growth Factor Receptor 1) in Preeclampsia

Cited by 45 publications

References 49 publications

Concentrations and immunostimulatory potential of circulating cell-free membrane-bound and membrane-unbound mitochondrial DNA in preeclampsia

Concentrations and immunostimulatory potential of circulating cell-free membrane-bound and membrane-unbound mitochondrial DNA in preeclampsia

Activation of a TLR9 mediated innate immune response in preeclampsia

Role of the NLRP3 Inflammasome in Preeclampsia

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