The role of immune cells and mediators in preeclampsia

Deer, Evangeline; Herrock, Owen; Campbell, Nathan; Cornelius, Denise C.; Fitzgerald, Sarah; Amaral, Lorena M.; LaMarca, Babbette

doi:10.1038/s41581-022-00670-0

Cited by 81 publications

(48 citation statements)

References 202 publications

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“…In a healthy pregnancy, macrophages are the second largest leukocytes at the maternal-fetal interface and have been shown to play an important role in remodeling spiral arteries and placental development ( 40 ). However, macrophages are also the key regulators of inflammation ( 8 ).…”

Section: Discussionmentioning

confidence: 99%

“…The deterioration of the placental proinflammatory environment is characterized by placental inflammatory cell infiltration and macrophage phenotype changes, with placental macrophages as the main producers of TNF-α ( 41 ). Proinflammatory M1 macrophages secreting TNF-α, interleukin-1β (IL-1β), IL-12, and IL-18 are more abundant in the placenta, decidua, and surrounding uterine spiral arteries of women with metabolic abnormalities than in tissues from healthy pregnancies ( 40 ). Dysregulation of macrophage polarization and secretion of proinflammatory factors are responsible for reduced trophoblast cell invasion and inadequate spiral artery remodeling in preeclampsia ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

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Lachnospiraceae -derived butyrate mediates protection of high fermentable fiber against placental inflammation in gestational diabetes mellitus

Huang,

Chen,

Cui

et al. 2023

Sci. Adv.

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Inflammation-associated insulin resistance is a key trigger of gestational diabetes mellitus (GDM), but the underlying mechanisms and effective interventions remain unclear. Here, we report the association of placental inflammation (tumor necrosis factor–α) and abnormal maternal glucose metabolism in patients with GDM, and a high fermentable dietary fiber (HFDF; konjac ) could reduce GDM development through gut flora–short-chain fatty acid–placental inflammation axis in GDM mouse model. Mechanistically, HFDF increases abundances of Lachnospiraceae and butyrate, reduces placental-derived inflammation by enhancing gut barrier and inhibiting the transfer of bacterial-derived lipopolysaccharide, and ultimately resists high-fat diet–induced insulin resistance. Lachnospiraceae and butyrate have similar anti-GDM and anti–placental inflammation effects, and they can ameliorate placental function and pregnancy outcome effects probably by dampening placental immune dysfunction. These findings demonstrate the involvement of important placental inflammation–related mechanisms in the progression of GDM and the great potential of HFDFs to reduce susceptibility to GDM through gut-flora-placenta axis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lachnospiraceae -derived butyrate mediates protection of high fermentable fiber against placental inflammation in gestational diabetes mellitus

Huang,

Chen,

Cui

et al. 2023

Sci. Adv.

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“…RUPP also leads to dysregulated immune responses [164]. Dysregulation of immune cells such as regulatory T cells, macrophages, natural killer cells, and neutrophils, as well as ferroptosis and autophagy in the fetoplacental tissues, have also been implicated in the pathology of preeclampsia [165][166][167][168]. Immune-suppressive FIGURE 7 A diagrammatic presentation of the potential effect of ADE101 on placental ischemia-mediated endothelial dysfunction and fetal growth restriction.…”

Section: Discussionmentioning

confidence: 99%

“…RUPP also leads to dysregulated immune responses [164]. Dysregulation of immune cells such as regulatory T cells, macrophages, natural killer cells, and neutrophils, as well as ferroptosis and autophagy in the fetoplacental tissues, have also been implicated in the pathology of preeclampsia [165–168]. Immune-suppressive regulatory T cells (Tregs) are known to play an essential role in sustaining tolerance to the semi-allogeneic fetus during pregnancy [169], while maternal CD8 + killer T cells develop an exhaustion-prone phenotype during pregnancy [170–173].…”

Section: Discussionmentioning

confidence: 99%

Stable adrenomedullin analog mitigates placental ischemia-induced hypertension and fetal growth restriction in rats

Chang

Cai²,

Hsu³

2023

Journal of Hypertension

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Objective(s):Preeclampsia is a heterogeneous hypertensive disorder of pregnancy. It affects multiorgans and may lead to fetal growth restriction, organ failure, seizure, and maternal death. Unfortunately, current treatments are ineffective at delaying the progression of preeclampsia even for a few days. Clinicians are often forced to deliver preterm fetus if severe preeclampsia occurred early during pregnancy, leading to premature birth-associated complications. Preeclampsia has been associated with defects at the maternal–fetal interface and maternal vascular dysfunction. Of interest, the adrenomedullin peptide and its cognate receptors, calcitonin receptor-like receptor (CLR)/ receptor activity-modifying protein (RAMP) receptor complexes, have been shown to be important regulators of cardiovascular adaptation and feto-placental development during pregnancy. Although the exact role of adrenomedullin-CLR/RAMP signaling in different feto-maternal compartments during pregnancy and how adrenomedullin expression affects preeclampsia development remains to be clarified, we hypothesized that the sustained activation of CLR/RAMP receptors could be a promising strategy to mitigate placental ischemia-associated vascular dysfunction and fetal growth restriction under preeclampsia-like conditionsMethods:To explore this possibility, we have developed a stable adrenomedullin analog, ADE101, and investigated its effects on human lymphatic microvascular endothelial (HLME) cell proliferation, hemodynamics, and pregnancy outcomes in pregnant rats with reduced uteroplacental perfusion pressure (RUPP) induced by clipping of uterine arteries on gestation day 14Results:The ADE101 analog has a potent effect on CLR/RAMP2 receptor activation, and an enhanced stimulatory effect on HLME cell proliferation compared to wild-type peptides. ADE101 also exhibits a lasting effect on hemodynamics in normal and hypertensive rats. In addition, studies using the RUPP model showed that ADE101 significantly reduces placental ischemia-induced hypertension and fetal growth restriction in a dose-dependent manner. Infusion of ADE101 increased the weight of fetuses and placentas in RUPP animals to 252% and 202% of that of RUPP controls, respectively.Conclusions:These data suggested that long-acting adrenomedullin analog could be useful for quenching hypertension as well as the vascular ischemia-associated organ damages in preeclamptic patients.

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“…Patients with PE have activation of both the innate and adaptive arms of the immune system which induce a feed-forward mechanism for inflammation (Murray et al, 2021). Cytolytic NK cells, macrophages, dendritic cells induce tissue damage and vascular dysfunction in PE while activating Th cells through antigen presentation (Deer et al, 2023). Moreover, patients with PE have activated Th cells and activated B cells producing agonistic antibodies against the angiotensin II type 1 receptor (AT1-AA) which lead to antigen specific mechanisms of cell destruction and tissue damage (LaMarca et al, 2016).…”

Section: Third Trimester Of Pregnancy and Parturitionmentioning

confidence: 99%

Setting a stage: Inflammation during preeclampsia and postpartum

2023

Self Cite

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Preeclampsia (PE) is a leading cause of maternal and fetal mortality worldwide. The immune system plays a critical role in normal pregnancy progression; however, inappropriate inflammatory responses have been consistently linked with PE pathophysiology. This inflammatory phenotype consists of activation of the innate immune system, adaptive immune system, and increased inflammatory mediators in circulation. Moreover, recent studies have shown that the inflammatory profile seen in PE persists into the postpartum period. This manuscript aims to highlight recent advances in research relating to inflammation in PE as well as the inflammation that persists postpartum in women after a PE pregnancy. With the advent of the COVID-19 pandemic, there has been an increase in obstetric disorders associated with COVID-19 infection during pregnancy. This manuscript also aims to shed light on the relationship between COVID-19 infection during pregnancy and the increased incidence of PE in these women.

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The role of immune cells and mediators in preeclampsia

Cited by 81 publications

References 202 publications

Lachnospiraceae -derived butyrate mediates protection of high fermentable fiber against placental inflammation in gestational diabetes mellitus

Lachnospiraceae -derived butyrate mediates protection of high fermentable fiber against placental inflammation in gestational diabetes mellitus

Stable adrenomedullin analog mitigates placental ischemia-induced hypertension and fetal growth restriction in rats

Setting a stage: Inflammation during preeclampsia and postpartum

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