Role of Tumor Necrosis Factor-α and Natural Killer Cells in Uterine Artery Function and Pregnancy Outcome in the Stroke-Prone Spontaneously Hypertensive Rat

Small, Hamish J.; Nosalski, Ryszard; Morgan, Hannah L.; Beattie, Elisabeth; Guzik, Tomasz J.; Graham, Delyth; Delles, Christian

doi:10.1161/hypertensionaha.116.07933

Cited by 24 publications

(20 citation statements)

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“…Human studies of NK cell subsets have shown that the cNK cell subset is highly cytolytic and produces significant amounts of IFN- γ and TNF- α [11,15]. Small et al [30] recently published a study demonstrating that NK cells are the major producers of TNF- α in a stroke-prone spontaneous hypertensive rat model. In our current study, depletion of NK cells with anti-ASGM1 also resulted in a depletion of serum and placental TNF- α (Figures 4 and 5) further strengthening the notion of cNK cell involvement in hypertensive pregnancy disorders.…”

Section: Discussionmentioning

confidence: 99%

Natural killer cells mediate pathophysiology in response to reduced uterine perfusion pressure

et al. 2017

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Preeclampsia is associated with hypertension, small-for-gestational-age babies, and increased cytolytic natural killer (NK) cells. The specific role of cytolytic NK cells in the pathophysiology of preeclampsia has not been clearly defined. We hypothesized that Reduced Uterine Perfusion Pressure (RUPP) stimulates proliferation and cytolytic activation of NK cells, and that reducing NK cells in RUPP would prevent hypertension, intrauterine growth restriction, and inflammation in response to placental ischemia. RUPP was induced on gestation day (GD) 14 in pregnant rats. NK cells were depleted by i.p. administration of anti-asialo GM1 antibody on GDs 15 and 17. Placental and circulating NK cells were quantified via flow cytometry, mean arterial pressure (MAP), fetal weights, and cytokines were measured on GD 19. Total placental NK cells were 7.4±2% of gated cells in normal pregnant (NP; n=10) and 16.5± 3% of gated cells in RUPP (n=10) rats. Furthermore, cytolytic placental NK cells also increased in RUPP. Depletion of NK cells in RUPP (RUPP + anti-ASGM1) significantly improved MAP and fetal weights. MAP was 108± 2 mmHg in NP, 125± 2 mmHg in RUPP, and 112± 2 mmHg in RUPP + anti-ASGM1 (n=12). Fetal weight was 2.32 ± 0.05 in NP, 1.8± 0.04g in RUPP, and increased to 2.0± 0.04g in RUPP + anti-ASGM1. Placental interferon-γ (IFN-γ) was 40.4± 5.2 pg/mg in NP, 72.17± 3.2 pg/mg in RUPP, and 44.0± 6.5 pg/mg in RUPP + anti-ASGM1 (P<0.05). Placental tumor necrosis factor-α (TNF-α) was 17.9± 1.7 pg/mg in NP, 23.9± 2.2 pg/mg in RUPP, and 12.9± 2.3 pg/mg in RUPP + anti-ASGM1 (P<0.05). Depletion of NK cells significantly lowered MAP, intrauterine growth restriction, and inflammation in RUPP rats indicating that cytolytic NK cells are important in preeclampsia pathophysiology.

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Section: Discussionmentioning

confidence: 99%

Natural killer cells mediate pathophysiology in response to reduced uterine perfusion pressure

et al. 2017

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“…Natural killer (NK) cells are the major innate lymphocytes [ 11 , 12 , 13 , 14 ]. NK cells mediate cytotoxicity [ 15 , 16 , 17 , 18 , 19 ] and produce significant quantities of inflammatory cytokines, including interferon-γ (IFN-γ) [ 20 , 21 , 22 , 23 , 24 ] and tumor necrosis factor-alpha (TNF-α) [ 25 , 26 , 27 , 28 ]. Our knowledge about the molecular basis of the development and functions of NK cells is progressing rapidly.…”

Section: Introductionmentioning

confidence: 99%

Tissue-Resident NK Cells: Development, Maturation, and Clinical Relevance

Hashemi

Malarkannan

2020

Cancers

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Natural killer (NK) cells belong to type 1 innate lymphoid cells (ILC1) and are essential in killing infected or transformed cells. NK cells mediate their effector functions using non-clonotypic germ-line-encoded activation receptors. The utilization of non-polymorphic and conserved activating receptors promoted the conceptual dogma that NK cells are homogeneous with limited but focused immune functions. However, emerging studies reveal that NK cells are highly heterogeneous with divergent immune functions. A distinct combination of several activation and inhibitory receptors form a diverse array of NK cell subsets in both humans and mice. Importantly, one of the central factors that determine NK cell heterogeneity and their divergent functions is their tissue residency. Decades of studies provided strong support that NK cells develop in the bone marrow. However, evolving evidence supports the notion that NK cells also develop and differentiate in tissues. Here, we summarize the molecular basis, phenotypic signatures, and functions of tissue-resident NK cells and compare them with conventional NK cells.

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“…An increased number of NK cells are also observed in the circulation of pregnant hypertensive rats [62]. Moreover, depletion of NK cells leads to protection from Ang II-induced vascular dysfunction [63].…”

Section: Link Between Immune Cells and Hypertensionmentioning

confidence: 99%

“…Studies of Taherzadeh et al have shown that NK gene complex is an important determinant to genetically determined sensitivity to develop HT and associated vascular remodelling in L-NAME-induced HT in mice [ 61 ]. An increased number of NK cells are also observed in the circulation of pregnant hypertensive rats [ 62 ]. Moreover, depletion of NK cells leads to protection from Ang II-induced vascular dysfunction [ 63 ].…”

Section: Link Between Immune Cells and Hypertensionmentioning

confidence: 99%

“…Tumour necrosis factor alpha (TNF-α) is produced by many cell types including immune cells, vascular cells and adipocytes [ 67 ]. Various studies have shown that HT is associated with elevated production of TNF-α by different immune cells and a subsequent rise is observed in the circulation [ 27 , 62 , 68 , 69 ]. Blockade of AT1 receptors in patients with HT results in a significant reduction of circulating levels of TNF-α.…”

Section: Cytokines As Key Mediators In Hypertensionmentioning

confidence: 99%

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Novel Immune Mechanisms in Hypertension and Cardiovascular Risk

Nosalski

McGinnigle

Siedliński

et al. 2017

Curr Cardiovasc Risk Rep

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Purpose of ReviewHypertension is a common disorder with substantial impact on public health due to highly elevated cardiovascular risk. The mechanisms still remain unclear and treatments are not sufficient to reduce risk in majority of patients. Inflammatory mechanisms may provide an important mechanism linking hypertension and cardiovascular risk. We aim to review newly identified immune and inflammatory mechanisms of hypertension with focus on their potential therapeutic impact.Recent FindingsIn addition to the established role of the vasculature, kidneys and central nervous system in pathogenesis of hypertension, low-grade inflammation contributes to this disorder as indicated by experimental models and GWAS studies pointing to SH2B3 immune gene as top key driver of hypertension. Immune responses in hypertension are greatly driven by neoantigens generated by oxidative stress and modulated by chemokines such as RANTES, IP-10 and microRNAs including miR-21 and miR-155 with other molecules under investigation. Cells of both innate and adoptive immune system infiltrate vasculature and kidneys, affecting their function by releasing pro-inflammatory mediators and reactive oxygen species.SummaryImmune and inflammatory mechanisms of hypertension provide a link between high blood pressure and increased cardiovascular risk, and reduction of blood pressure without attention to these underlying mechanisms is not sufficient to reduce risk.

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Role of Tumor Necrosis Factor-α and Natural Killer Cells in Uterine Artery Function and Pregnancy Outcome in the Stroke-Prone Spontaneously Hypertensive Rat

Abstract: Supplemental Digital Content is available in the text.

Cited by 24 publications

References 56 publications

Natural killer cells mediate pathophysiology in response to reduced uterine perfusion pressure

Natural killer cells mediate pathophysiology in response to reduced uterine perfusion pressure

Tissue-Resident NK Cells: Development, Maturation, and Clinical Relevance

Novel Immune Mechanisms in Hypertension and Cardiovascular Risk

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