Activation of a TLR9 mediated innate immune response in preeclampsia

Abstract

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.

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

“…Although concentrations of CFCmtDNA was reduced in our cohort of women with preeclampsia, plasma from these subjects induced greater TLR-9 activity as monitored using SEAP reporter 293 cells expressing the human TLR-9 gene. This finding is in agreement with previous studies showing increased TLR-9 activity in women with preeclampsia at time of diagnosis 12 . Our study extends these findings demonstrating greater TLR-9 activity in the presence of lower concentrations of CFCmtDNA in plasma from women with preeclampsia.…”

“…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 . Cross-sectional and case-control studies have reported increased CFCmtDNA copy number in serum and whole blood from women with preeclampsia in the third trimester 13, 14 or at time of delivery 15 .…”

Mechanisms of Endothelial Dysfunction in Pre-eclampsia and Gestational Diabetes Mellitus: Windows Into Future Cardiometabolic Health?

“…MtDNA can instigate a pro-inflammatory response in the maternal circulation by binding to toll-like receptor 9 (TLR-9) on immune cells. Recent work in our group established that pathogenic plasma mediators (including mtDNA) of PE increased TLR-9 activation with ensuing neutrophil activation (75,76). MtDNA has also been shown to activate the NLRP3 inflammasome leading to cleavage of procaspase-1 and the resulting release of pro-inflammatory cytokines IL-1β and IL-18, which in turn can inflict endothelial damage (77,78).…”

Associations between pre-pregnancy body mass index and gestational weight gain with pregnancy outcomes in women with polycystic ovary syndrome

“…Gestational hypertension (GH) was defined as de novo hypertension, if an individual exhibited a systolic blood pressure ≥ 140 mmHg and, or diastolic blood pressure ≥ 90 mmHg, after 20 weeks of pregnancy [ 12 ], whereas preeclampsia (PE) was defined by the onset of hypertension and proteinuria, after 20 weeks of gestation [ 13 ]. Gestational diabetes mellitus (GDM) diagnosis was based on the result of a standard 75 g oral glucose tolerance test between 24 and 28 weeks of gestation, if any one of the following criteria was met: plasma glucose ≥ 5.1 mmo/L, ≥ 10.0 mmol/L, and ≥ 8.5 mmol/L for fasting, 1 and 2 h respectively.…”