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Multicenter Study
. 2019 Apr 11;9(1):5920.
doi: 10.1038/s41598-019-42551-w.

Activation of a TLR9 mediated innate immune response in preeclampsia

Rachel D Williamson  1 , Fergus P McCarthy  2 , Louise C Kenny  2   3 , Cathal M McCarthy  2   4
Affiliations
Multicenter Study

Activation of a TLR9 mediated innate immune response in preeclampsia

Rachel D Williamson et al. Sci Rep. .

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.

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Conflict of interest statement

L.C. Kenny is a minority shareholder in Metabolomic Diagnostics, a campus-based spin-out that has licensed technology concerning the use of metabolomics biomarkers in the prediction of preeclampsia.

Figures

Figure 1
Figure 1
TLR9 activity and downstream markers of neutrophil activation did not alter at 15 weeks’ gestation. There was no significant increase in TLR9 activity (a) or neutrophil activation markers Calprotectin (b), MPO, (c) MMP-8 (d) and IL-8 (e) at 15 weeks’ gestation between cases and controls.
Figure 2
Figure 2
TLR9 activity and downstream markers of neutrophil activation did not alter at 20 weeks’ gestation. There was no significant increase in TLR9 activity (a) or neutrophil activation markers Calprotectin (b), MMP-8 (d) and IL-8 (e) at 20 weeks’ gestation between cases and controls. MPO expression (c) is significantly increased in cases compared with controls (P = 0.02).
Figure 3
Figure 3
Circulating plasma mediators activate a TRL9-mediated innate immune response in preeclampsia at TOD. TLR-9 activity (a), Calprotectin (b), MPO (c), and IL-8 (e) are significantly increased at time of disease in cases compared to controls (P = 0.01). There was no significant increase in MMP-8 at TOD in cases in comparison to controls.
Figure 4
Figure 4
Normal pregnancy did not activate a TLR9 mediated innate immune response. There was no significant increase in TLR9 activity (a), Calprotectin (b), MPO (c) in healthy control pregnancies across gestation. MMP8 (d) is significantly reduced at term pregnancies (P = 0.01), while IL-8 (e) showed no significant difference across gestation in healthy control pregnancies.
Figure 5
Figure 5
Neutrophil activation markers are increased across pregnancyin preeclampsia. TLR9 activity (a), Calprotectin (b), are both significantly increased across gestation in cases with preeclampsia (P = 0.01). There was no significant increase in neutrophil activation markers MPO (c), MMP8 (d) and IL-8 (e) across gestation in cases with preeclampsia.
See this image and copyright information in PMC

References

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