LPS-induced maternal inflammation promotes fetal leukocyte recruitment and prenatal organ infiltration in mice

Hudalla, Hannes; Karenberg, Katinka; Kuon, Ruben; Pöschl, Johannes; Tschada, R.; Frommhold, David

doi:10.1038/s41390-018-0030-z

Cited by 41 publications

(45 citation statements)

References 31 publications

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“…Our data agrees with several other reports of LPS-induced inflammation and PTB in a mouse model [ 61 , 62 , 63 ]. In addition, we report that this inflammation is also associated with elevated NHERF1.…”

Section: Discussionsupporting

confidence: 94%

“…Typically, NHERF1 is a PDZ-scaffolding protein that organizes functional complexes and modulates kinase activities to accurately coordinate specific signaling pathways [ 59 ]. Previous studies have shown that NHERF1 expression is increased in inflammatory carcinogenic tissues [ 60 , 61 ]. Similarly, we observed higher NHERF1 gene expression in human fetal membranes from TL and PTB that are triggered by inflammation compared to membranes not in labor.…”

Section: Discussionmentioning

confidence: 99%

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Sodium Hydrogen Exchanger Regulatory Factor-1 (NHERF1) Regulates Fetal Membrane Inflammation

Kammala

Sheller‐Miller

Radnaa

et al. 2020

IJMS

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The fetal inflammatory response, a key contributor of infection-associated preterm birth (PTB), is mediated by nuclear factor kappa B (NF-kB) activation. Na+/H+ exchanger regulatory factor-1 (NHERF1) is an adapter protein that can regulate intracellular signal transduction and thus influence NF-kB activation. Accordingly, NHERF1 has been reported to enhance proinflammatory cytokine release and amplify inflammation in a NF-kB-dependent fashion in different cell types. The objective of this study was to examine the role of NHERF1 in regulating fetal membrane inflammation during PTB. We evaluated the levels of NHERF1 in human fetal membranes from term labor (TL), term not in labor (TNIL), and PTB and in a CD1 mouse model of PTB induced by lipopolysaccharide (LPS). Additionally, primary cultures of fetal membrane cells were treated with LPS, and NHERF1 expression and cytokine production were evaluated. Gene silencing methods using small interfering RNA targeting NHERF1 were used to determine the functional relevance of NHERF1 in primary cultures. NHERF1 expression was significantly (p < 0.001) higher in TL and PTB membranes compared to TNIL membranes, and this coincided with enhanced (p < 0.01) interleukin (IL)-6 and IL-8 expression levels. LPS-treated animals delivering PTB had increased levels of NHERF1, IL-6, and IL-8 compared to phosphate-buffered saline (PBS; control) animals. Silencing of NHERF1 expression resulted in a significant reduction in NF-kB activation and IL-6 and IL-8 production as well as increased IL-10 production. In conclusion, downregulation of NHERF1 increased anti-inflammatory IL-10, and reducing NHERF1 expression could be a potential therapeutic strategy to reduce the risk of infection/inflammation associated with PTB.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Sodium Hydrogen Exchanger Regulatory Factor-1 (NHERF1) Regulates Fetal Membrane Inflammation

Kammala

Sheller‐Miller

Radnaa

et al. 2020

IJMS

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“…[61][62][63] Thus, even in the absence of fetal viral infection or severe maternal symptoms, placental infection can trigger a fetal inflammatory response, leading to multiorgan system damage and predisposition for negative developmental consequences (Table 2). [64][65][66][67][68][69][70] There is strong evidence to suggest that maternal inflammation associated with SARS-CoV-2 may confer long-term risk of neuropsychiatric disorders in children. MIA has been described as a "neurodevelopmental disease primer" that increases susceptibility of individuals to interacting genetic and environmental risk factors that can trigger neuro-or psychopathology later in life.…”

Section: Discussionmentioning

confidence: 99%

COVID‐19 in pregnancy: Placental and neonatal involvement

Prochaska

Jang

Burd

2020

American J Rep Immunol

102

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The first cases of severe pneumonia from a novel coronavirus were reported in Wuhan, China in December 2019. 10 Since then, the virus has been identified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection causes fevers, cough, dyspnea, myalgias, pharyngitis, diarrhea, pneumonia, acute respiratory distress syndrome, multisystem organ failure, cytokine storm, endothelial damage, and thrombotic events. 2,3,11-13 It has infected over 12 million people and caused over 550 000 deaths across the globe. 1 The case fatality rate is estimated at 2.3% among the entire population. 14 Recent observations show that the majority of pregnant women are asymptomatic or have mild disease based on the criteria proposed by Wu et al. 14-16 Nevertheless, any infection during pregnancy has potential risks. A recent review of obstetric cases found that 3% of pregnant women with SARS-CoV-2 required intensive care. 17 There have also been cases of preterm labor and perinatal death in the setting of maternal SARS-CoV-2 infection. It is uncertain whether the virus can be vertically transmitted from mother to neonate. Given that SARS-CoV-2 causes inflammatory, coagulation, and endothelial changes, investigating placental and fetal involvement during infection is crucial to providing guidance and care to pregnant patients. Coronaviruses are enveloped positive-sense single-stranded RNA viruses that infect both humans and animals. 18 Human coronaviruses typically cause mild upper and lower respiratory infections, although they can present as severe pneumonia or bronchiolitis. 7,18 Gastrointestinal symptoms can also occur with infection. Coronaviruses were believed to have little clinical significance until the 21st century. Since 2002, three novel coronaviruses have been described: SARS-CoV in 2002, Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, and SARS-CoV-2 in 2019. SARS-CoV appears to primarily target ciliated epithelial cells via the angiotension-converting enzyme 2 (ACE2) receptor. ACE2 is expressed in the cardiovascular system, gut tissue, adipose tissue, lungs, kidneys, the placenta, and fetal tissue. 19-21 SARS-CoV-2 also binds to ACE2 in order to enter cells. 19,20,22 The clinical presentation of coronaviruses is likely due to both direct cell injury and host response.

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“…Although IA inflammation is restricted to the fetal-maternal interface and the amniotic fluid, pathogenassociated IA inflammation leads to inflammatory responses in multiple other fetal organs including the brain, lungs, skin, and gut in humans and animals (5,6). Much of the work investigating infection-driven inflammation at the fetal-maternal interface has focused on the maternally derived decidua and/or the fetus-derived fetal membranes (7)(8)(9)(10)(11). Yet, the fetus-derived placental villi, which is in contact with the fetal membranes and invades into the maternal decidua, comprises the bulk of the fetal-maternal interface by mass.…”

Section: Introductionmentioning

confidence: 99%

Immune Cells in the Placental Villi Contribute to Intra-amniotic Inflammation

et al. 2020

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Intra-amniotic (IA) inflammation is associated with significant morbidities for both the mother and the fetus. Prior studies have illustrated many of the effects of IA inflammation on the uterine lining (decidua) and membranous layers of the placenta at the fetal-maternal interface. However, much less is known about the immunological response occurring within the villous placenta. Using a rhesus macaque model of lipopolysaccharide (LPS)-induced IA inflammation, we showed that pregnancy-matched choriodecidua and villi have distinct immunological profiles in rhesus pregnancies. In the choriodecidua, we show that the abundance of neutrophils, multiple populations of antigen-presenting cells, and two populations of natural killer (NK) cells changes with prenatal IA LPS exposure. In contrast, in immune cells within the villous placenta we observed alterations in the abundance of B cells, monocytes, and CD8 T cells. Prior work has illustrated that IA inflammation leads to an increase in tumor necrosis factor alpha (TNFα) at the fetal-maternal interface. In this study, pretreatment with a TNFα blockade partially reversed inflammation in the placental villi. Furthermore, we report that immune cells in the villous placenta sensed LPS during our experimental window, and subsequently activated T cells to produce proinflammatory cytokines. Moreover, this study is the first report of memory T cells in third-trimester non-human primate placental villi and provides evidence that manipulation of immune cells in the villi at the fetal-maternal interface should be considered as a potential therapeutic target for IA inflammation.

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LPS-induced maternal inflammation promotes fetal leukocyte recruitment and prenatal organ infiltration in mice

Abstract: LPS-induced maternal endotoxemia promotes IUFD, PTB, and fetal leukocyte recruitment depending on gestational age. Our proposed model may serve as a platform to test novel perinatal immune modulators.

Cited by 41 publications

References 31 publications

Sodium Hydrogen Exchanger Regulatory Factor-1 (NHERF1) Regulates Fetal Membrane Inflammation

Sodium Hydrogen Exchanger Regulatory Factor-1 (NHERF1) Regulates Fetal Membrane Inflammation

COVID‐19 in pregnancy: Placental and neonatal involvement

Immune Cells in the Placental Villi Contribute to Intra-amniotic Inflammation

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