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Published on: January 26, 2024
Toll-like receptor 9 activation: a novel mechanism linking placenta-derived mitochondrial DNA and vascular
Styliani Goulopoulou1, Takayuki Matsumoto, Gisele F Bomfim
1Department of Physiology, Georgia Health Sciences University, Augusta, GA, USA. sgoulopoulou@georgiahealth.edu
Abstract:
Emerging evidence suggests that in addition to being the 'power houses' of our cells, mitochondria facilitate effector responses of the immune system. Cell death and injury result in the release of mtDNA (mitochondrial DNA) that acts via TLR9 (Toll-like receptor 9), a pattern recognition receptor of the immune system which detects bacterial and viral DNA but not vertebrate DNA. The ability of mtDNA to activate TLR9 in a similar fashion to bacterial DNA stems from evolutionarily conserved similarities between bacteria and mitochondria. mtDNA may be the trigger of systemic inflammation in pathologies associated with abnormal cell death. PE (pre-eclampsia) is a hypertensive disorder of pregnancy with devastating maternal and fetal consequences. The aetiology of PE is unknown and removal of the placenta is the only effective cure. Placentas from women with PE show exaggerated necrosis of trophoblast cells, and circulating levels of mtDNA are higher in pregnancies with PE. Accordingly, we propose the hypothesis that exaggerated necrosis of trophoblast cells results in the release of mtDNA, which stimulates TLR9 to mount an immune response and to produce systemic maternal inflammation and vascular dysfunction that lead to hypertension and IUGR (intra-uterine growth restriction). The proposed hypothesis implicates mtDNA in the development of PE via activation of the immune system and may have important preventative and therapeutic implications, because circulating mtDNA may be potential markers of early detection of PE, and anti-TLR9 treatments may be promising in the management of the disease.
Insights
Mitochondrial DNA (mtDNA) released from dying placental cells may trigger pre-eclampsia by activating the immune system via Toll-like receptor 9 (TLR9), causing inflammation and hypertension.
Area of Science:
- Immunology
- Cell Biology
- Obstetrics
Background:
- Mitochondria, known as cell powerhouses, also play a role in immune responses.
- Release of mitochondrial DNA (mtDNA) during cell death can activate immune receptors like Toll-like receptor 9 (TLR9).
- Pre-eclampsia (PE) is a pregnancy disorder with unknown causes, characterized by hypertension and potential fetal growth restriction.
Purpose of the Study:
- To investigate the hypothesis that mtDNA released from necrotic trophoblast cells contributes to the pathogenesis of pre-eclampsia.
- To explore the role of mtDNA-TLR9 interaction in mediating maternal inflammation and vascular dysfunction in PE.
Main Methods:
- The study proposes a hypothesis based on existing evidence regarding mtDNA, TLR9, and PE.
- Analysis of placental tissue from PE patients showing increased trophoblast necrosis.
- Measurement of circulating mtDNA levels in pregnancies complicated by PE.
Main Results:
- Placentas from women with PE exhibit exaggerated trophoblast cell necrosis.
- Elevated levels of circulating mtDNA are observed in pregnancies affected by PE.
- mtDNA's structural similarity to bacterial DNA allows it to activate TLR9, similar to pathogen-associated molecular patterns.
Conclusions:
- mtDNA released from dying trophoblast cells may activate TLR9, initiating maternal immune responses and systemic inflammation.
- This immune activation could lead to the vascular dysfunction, hypertension, and intra-uterine growth restriction (IUGR) characteristic of PE.
- Circulating mtDNA may serve as a potential biomarker for early PE detection, and anti-TLR9 therapies could offer new treatment avenues.
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