Placental ischemia-stimulated T-helper 17 cells induce preeclampsia-associated cytolytic natural killer cells during pregnancy

Shields, Corbin A.; McCalmon, Maggie; Ibrahim, Tarek; White, Dakota; LaMarca, Babbette; Cornelius, Denise C.

doi:10.1152/ajpregu.00061.2018

Cited by 34 publications

(30 citation statements)

References 41 publications

(55 reference statements)

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“…We hypothesized that this was a result of increased ROS production, but treatment with TEMPOL had no effect on the NK cell activity (Shields et al. ). Since NK cells express the IL‐17 RC receptor and IL‐17, the major cytokine produced by T H 17 cells, is reported to be increased in PE women (Molvarec et al.…”

Section: Discussionmentioning

confidence: 99%

“…Single‐cell suspensions of placental leukocytes were prepared, as previously described (Shields et al. ). Briefly, one placenta from each rat was homogenized and filtered through a 70‐ μ m cell strainer and resuspended in 15 mL of Rosswell Park Memorial Institute medium (RPMI) (10% FBS).…”

Section: Methodsmentioning

confidence: 99%

“…Superoxide production in the placenta and renal cortex were measured using the lucigenin technique, as previously described by our lab (Shields et al. ). Briefly, rat placentas and 1 g of renal cortexes from NP and NP+IL‐17 rats were snap frozen in liquid nitrogen immediately after collection and stored at −80°C until further processing.…”

Section: Methodsmentioning

confidence: 99%

“…; Shields et al. ). However, the mechanism of how T H 17 cells activate NK cells during PE has not been investigated.…”

Section: Introductionmentioning

confidence: 97%

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Chronic infusion of interleukin‐17 promotes hypertension, activation of cytolytic natural killer cells, and vascular dysfunction in pregnant rats

et al. 2019

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Previous studies by our lab have established that placental‐ischemia stimulated T‐helper 17 cells ( T H 17s) cause increased cytolytic natural killer ( cNK ) cell proliferation and activation during pregnancy; however, the exact mechanism is unknown. The objective of this study was to investigate the role of interlukin 17 ( IL ‐17) in inducing cNK cell activation in pregnancy. We infused 150 pg/day of recombinant IL ‐17 into a subset of normal pregnant ( NP ) Sprague Dawley rats from gestation day ( GD ) 12–19 ( NP + IL ‐17). On GD 19, mean arterial pressure ( MAP ), fetal and placental weights, cytokines, cNK cell activation, cytotoxic enzymes, and vascular reactivity were assessed. MAP significantly increased from 99 ± 3 mmHg in NP to 120 ± 1 mmHg in NP + IL ‐17 ( P < 0.05). Fetal weight significantly decreased from 2.52 ± 0.04 g in NP to 2.32 ± 0.03 g in NP + IL ‐17 as did placental weight ( NP : 0.65 ± 0.03 g; NP + IL ‐17: 0.54 ± 0.01 g, P < 0.05). Plasma levels of TNF ‐ α increased to 281.4 ± 55.07 pg/ mL in NP + IL ‐17 from 145.3 ± 16.03 pg/ mL in NP ( P < 0.05) while placental levels of VEGF decreased from 74.2 ± 6.48 pg/mg in NP to 54.2 ± 3.19 pg/mg in NP + IL ‐17. Total NK cells were increased in the placenta ( NP : 14.3 ± 3.49%; NP + IL ‐17: 29.33 ± 2.76%, P < 0.05) as were cytolytic NK cells ( NP : 3.31 ± 1.25%; NP + IL ‐17: 13.41 ± 1.81%, P < 0.05). A similar trend was observed in circulating NK cells. Plasma granzyme K increased from 3.55 ± 2.29 pg/ mL in NP to 20.9 ± 7.76 pg/ mL in NP + IL ‐17 ( P < 0.05), and plasma granzyme B increased from 10.95 ± 0.64 pg/ mL in NP to 14.9 ± 0.98 pg/ mL in NP + IL ‐17( P < 0.05). In the plac...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…; Shields et al. ). However, the mechanism of how T H 17 cells activate NK cells during PE has not been investigated.…”

Section: Introductionmentioning

confidence: 97%

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Chronic infusion of interleukin‐17 promotes hypertension, activation of cytolytic natural killer cells, and vascular dysfunction in pregnant rats

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“…Moreover, western blot analysis performed by Ridley et al showed that KIR-3DL2 expression is regulated by NF-κB [ 71 ]. As was described before, uNKs through KIRs recognize trophoblasts; however, uNKs are generally secretory, not cytotoxic, but Shields et al showed that ischemia-induced Th17 may mediate polarization of NKs toward a cytotoxic phenotype [ 72 ]. Therefore, maybe physiological inflammation and hypoxia in uterus during placentation facilitate recognition of specific HLA by Th17, which mediate further progression of inflammation and induction of cytotoxic NKs, although this is only a hypothesis.…”

Section: Risk Factors and Genetic Ground Of Preeclampsiamentioning

confidence: 99%

The Role of NF-κB in Uterine Spiral Arteries Remodeling, Insight into the Cornerstone of Preeclampsia

Socha

Malinowski

Puk

et al. 2021

IJMS

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Preeclampsia is one of the three leading causes of maternal morbidity and mortality worldwide. It afflicts 2–8% of pregnancies and is the most common cause of gestational hypertension. This article is focused on nuclear factor kappa B (NF-κB), its role in normal and pathological spiral arteries remodelling and development of preeclampsia, with evaluation if it is a promising therapeutic target. NF-κB is a key mediator of placentation. Since insemination, it stimulates production of proinflammatory cytokines by the uterine epithelium, which leads to activation of macrophages, uterine natural killer cells (uNKs), and other leukocytes. The trophoblast/uNK/macrophage crosstalk is crucial for implantation and spiral arteries remodeling, and NF-κB regulates that process through modification of cytokine expression, as well as cell phenotype and function. In the course of preeclampsia, the remodeling processes is disturbed by excessive inflammation and increased NF-κB activation. The pathological remodeling leads to uteroplacental dysfunction, release of proinflammatory cytokines into the maternal circulation, endothelial stress, and development of preeclampsia. The analysis of genetic and environmental inductors of NF-κB helps to distinguish preeclampsia risk groups. Furthermore, a selective inhibition of NF-κB or NF-κB activating pathways alleviates symptoms of preeclampsia in rat models; therefore, this could be an efficient therapeutic option.

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Cellular immune responses in the pathophysiology of preeclampsia

Miller

Motomura

Galaz

et al. 2021

Journal of Leukocyte Biology

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Preeclampsia, defined as new‐onset hypertension accompanied by proteinuria occurring at 20 weeks of gestation or later, is a leading cause of perinatal morbidity and mortality worldwide. The pathophysiology of this major multi‐systemic syndrome includes defective deep placentation, oxidative stress, endothelial dysfunction, the presence of an anti‐angiogenic state, and intravascular inflammation, among others. In this review, we provide a comprehensive overview of the cellular immune responses involved in the pathogenesis of preeclampsia. Specifically, we summarize the role of innate and adaptive immune cells in the maternal circulation, reproductive tissues, and at the maternal‐fetal interface of women affected by this pregnancy complication. The major cellular subsets involved in the pathogenesis of preeclampsia are regulatory T cells, effector T cells, NK cells, monocytes, macrophages, and neutrophils. We also summarize the literature on those immune cells that have been less characterized in this clinical condition, such as γδ T cells, invariant natural killer T cells, dendritic cells, mast cells, and B cells. Moreover, we discuss in vivo studies utilizing a variety of animal models of preeclampsia to further support the role of immune cells in this disease. Finally, we highlight the existing gaps in knowledge of the immunobiology of preeclampsia that require further investigation. The goal of this review is to promote translational research leading to clinically relevant strategies that can improve adverse perinatal outcomes resulting from the obstetrical syndrome of preeclampsia.

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Placental ischemia-stimulated T-helper 17 cells induce preeclampsia-associated cytolytic natural killer cells during pregnancy

Cited by 34 publications

References 41 publications

Chronic infusion of interleukin‐17 promotes hypertension, activation of cytolytic natural killer cells, and vascular dysfunction in pregnant rats

Chronic infusion of interleukin‐17 promotes hypertension, activation of cytolytic natural killer cells, and vascular dysfunction in pregnant rats

The Role of NF-κB in Uterine Spiral Arteries Remodeling, Insight into the Cornerstone of Preeclampsia

Cellular immune responses in the pathophysiology of preeclampsia

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