scholarly journals Interleukin-17 signaling mediates cytolytic natural killer cell activation in response to placental ischemia

2020 ◽  
Vol 318 (6) ◽  
pp. R1036-R1046 ◽  
Author(s):  
Olivia K. Travis ◽  
Dakota White ◽  
Cedar Baik ◽  
Chelsea Giachelli ◽  
Willie Thompson ◽  
...  
Keyword(s):  
Natural Killer ◽  
Cell Activation ◽  
Killer Cell ◽  
Cytolytic Activity ◽  
Interleukin 17 ◽  
Inflammatory Protein ◽  
Uterine Perfusion ◽  
Nk Cytotoxicity ◽  
Placental Ischemia

T-helper (TH)17s, IL-17, and cytolytic natural killer cells (cNKs) are increased in preeclampsia and contribute to the hypertension, inflammation, and fetal growth restriction that occurs in response to placental ischemia in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. As IL-17 stimulates NK cytotoxicity in vitro, we tested the hypothesis that IL-17 inhibition in RUPP rats would decrease cNK activation as a mechanism to improve maternal and fetal outcomes. On gestation day (GD) 14, rats undergoing RUPP received a miniosmotic pump infusing IL-17RC (100 pg/day), a soluble IL-17 receptor (RUPP + IL-17RC). On GD19, mean arterial pressure (MAP) was measured in normal pregnant (NP), RUPP, and RUPP + IL-17RC rats ( n = 10–12/group), animals were euthanized, and blood and tissues were collected for analysis. MAP was 30% higher in RUPP compared with NP ( P < 0.0001) and was 12% lower in RUPP + IL-17RC ( P = 0.0007 vs. RUPP). Placental cytolytic NK cells were 132% higher in RUPP than in NP ( P = 0.04 vs. NP) and were normalized in RUPP + IL-17RC ( P = 0.03 vs. RUPP). Placental levels of TNF-α, a cNK-secreted cytokine, and macrophage inflammatory protein-3α (MIP-3α), a cNK chemokine, were higher in RUPP vs. NP and lower after IL-17 blockade. Placental VEGF was lower in RUPP vs. NP and was normalized in RUPP + IL-17RC. In vitro cytolytic activity of RUPP placental NKs was higher compared with NP and was blunted in RUPP + IL-17RC NKs. Finally, both fetal weight and placental weight were lower in RUPP compared with NP, and were improved in RUPP + IL-17RC. These data identify IL-17 as a mediator of cNK activation in response to placental ischemia during pregnancy.

Abstract P207: Mitochondrial Dysfunction And Natural Killer Cell Activation Stimulated By Il-17 Signaling From Th17 Cells In Response To Placental Ischemia During Pregnancy; Sarah Fitzgerald, Evangeline Deer, Owen Herrock, Tarek Ibrahim, Lorena Amaral, Denise Cornelius And Babbette Lamarca; 1 Department Of Pharmacology, University Of Mississippi Medical Center.

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Sarah Fitzgerald ◽  
Owen Herrock ◽  
Evangeline M Deer ◽  
Tarek Ibrahim ◽  
Babbette B Lamarca ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Th17 Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Medical Center ◽  
Killer Cell ◽  
Multisystem Disorder ◽  
Uterine Perfusion ◽  
Placental Ischemia

Preeclampsia (PE) is a multisystem disorder characterized by new onset hypertension associated with placental ischemia (PI), mitochondrial (mt) dysfunction, and an imbalance in T helper (TH) and Natural Killer (NK) cells during pregnancy. The reduced uterine perfusion pressure (RUPP) model is an established model for PE. We have previously shown an important role for IL-17 in hypertension and activation of NK cells in the RUPP rat. We don’t know the role for IL-17 or TH17 cells in contributing to NK cell mediated mt dysfunction and ROS associated with PI. Therefore, we hypothesize that hypertension in response to PI stimulated TH17 cells causes mt ROS mediated through IL-17 signaling to NK cells. On gestation day 12 (GD12) RUPP-induced TH17s (splenic CD4+/CD25- cells) were adoptively transferred (Ad-T) into normal pregnant (NP) rats. Recombinant mouse IL-17 receptor C (IL-17RC) (100 pg/day) was administered from GD14-19 via osmotic mini-pump. On GD19, samples were collected and mean arterial pressure (MAP) was measured. Mt respiration and mt ROS data was measured in isolated mt from renal and placental tissues using the Oxygraph 2K and fluorescent microplate reader, respectively. A one-way ANOVA with Bonferroni post hoc test was used for statistical analysis. MAP was increased in Ad-T rats (112 ± 0.72mmHg, n=14) compared to NP (92 ± 3.03mmHg, n=14) (p<0.05), and was lowered with IL-17RC (97.2± 2.14 mmHg, n=13). Circulating activated NK cells were significantly increased with Ad-T (3.326± 0.76 %gated, n=9) (p<0.0001) compared to NP (0.05± 0.05 %, n=11), and were attenuated with IL-17RC (0.42± 0.4 %, n=5) (p<0.01). Placental activated NK cells were significantly increased with Ad-T (2.5± 1.01 %, n=4) (p<0.05) compared to NP (0.03± 0.03 %, n=8) and were attenuated with IL-17RC (0.21± 0.12 %, n=4) (p<0.05). Renal mtROS increased in Ad-T (312.4 ± 44.7%, n=9) compared to NP (191.9 ± 20.5%, n=5). Placental mtROS significantly increased in Ad-T (312.5 ± 23.6%, n=9) (P<0.0005) compared to NP controls (134 ± 9.6%, n=5) (p<0.0001), and was decreased by administration of IL-17RC (174.5± 42.5 %, n=5) (p<0.0001). These data demonstrate that IL-17 signaling plays an important role in NK cell activation and tissue mt function in response to TH17 cells stimulated during PE.

Abstract P101: Interleukin 17 Signaling Mediates Cytolytic Natural Killer Cell Activation in Response to Placental Ischemia

Hypertension ◽  
2019 ◽  
Vol 74 (Suppl_1) ◽  
Author(s):  
Denise C Cornelius ◽  
Olivia K Travis ◽  
Dakota White ◽  
Cedar H Baik ◽  
Willie L Thompson ◽  
...  
Keyword(s):  
Natural Killer Cell ◽  
Natural Killer ◽  
Cell Activation ◽  
Killer Cell ◽  
Interleukin 17 ◽  
Natural Killer Cell Activation ◽  
Placental Ischemia

Abstract 26: IL-17 Causes Hypertension, Reduced Fetal Weight And Natural Killer Cell Activation In The Absence Of T Cells

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Sarah J Fitzgerald ◽  
James Hogg ◽  
Evangeline Deer ◽  
Nathan Campbell ◽  
Owen Herrock ◽  
...  
Keyword(s):  
T Cells ◽  
Natural Killer ◽  
Rat Model ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Interleukin 17 ◽  
Sprague Dawley ◽  
Th Cells ◽  
Atp Production

Preeclampsia (PE) is characterized by new onset hypertension (HTN), intrauterine growth restriction (IUGR), multi-organ dysfunction, and is associated with increased inflammatory cytokines, such as interleukin 17 (IL-17). More recent studies demonstrate a role for mitochondrial (mt) dysfunction/mtROS in the pathogenesis of PE. Although we have shown T helper cells from a rat model of PE cause HTN and mt dysfunction the causative factors for mt dysfunction are still being identified. In addition, we have shown that IL-17 cause HTN, IUGR and activate natural killer (NK) cells, and cause mt dysfunction in pregnant Sprague Dawley rats. However, in our previous studies we couldn’t differentiate the effect of activated TH cells versus IL-17 to cause these characteristics of PE. The athymic nude rat model lacks mature T cells but does have other components of the immune system, and will thus allow us to examine the role of IL-17 in the absence of TH cells in the pathophysiology of PE. We hypothesize that in the absence of T cells IL-17 induces HTN, NK cell activation and IUGR which is associated with renal and placental mt dysfunction during pregnancy. To test our hypothesis, IL-17 (150 pg/day) was infused via osmotic minipumps inserted on gestation day (GD) 14. Blood pressure (MAP) and mt function were measured on GD19 and were compared to untreated pregnant (NP) athymic nude rats. In response to IL-17; MAP increased from 95±4mmHg in NP(n=6) to 115±2 in NP+IL-17(n=6) (p<0.001); pup weight decreased from 1.46±0.2 g in NP (n=6) to 0.98±0.07g in NP+IL-17 (n=6) (p<0.05); NK cell activation increased from 0±0 %lymphocytes in NP (n=3) to 0.4±0.1% lymphocytes in NP+IL-17 rats (n=6). Interestingly, placental mtROS reduced 54% fold compared to NP and renal mtROS reduced 51.2% compared to NP. ATP production increased from 15.53±1.6 pmol of O2/sec/mg in NP (n=3) to 105.5±91 pmol of O2/sec/mg in NP+IL-17 (n=3) in the placenta, and from 1196±460 pmol of O2/sec/mg in NP (n=4) to 2016±951 pmol of O2/sec/mg NP+IL17 (n=4) in the kidney. These results show that although IL-17 induces HTN, IUGR, and NK cell activation independent of T cells, T cells are necessary for reduced mitochondrial function observed in PE and in rat models of placental ischemia.

scholarly journals SARS-CoV-2 Spike 1 Protein Controls Natural Killer Cell Activation via the HLA-E/NKG2A Pathway

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1975 ◽  
Author(s):  
Daria Bortolotti ◽  
Valentina Gentili ◽  
Sabrina Rizzo ◽  
Antonella Rotola ◽  
Roberta Rizzo
Keyword(s):  
Epithelial Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Lung Epithelial Cells ◽  
Lung Epithelial ◽  
Spike Proteins

Natural killer cells are important in the control of viral infections. However, the role of NK cells during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has previously not been identified. Peripheral blood NK cells from SARS-CoV and SARS-CoV-2 naïve subjects were evaluated for their activation, degranulation, and interferon-gamma expression in the presence of SARS-CoV and SARS-CoV-2 spike proteins. K562 and lung epithelial cells were transfected with spike proteins and co-cultured with NK cells. The analysis was performed by flow cytometry and immune fluorescence. SARS-CoV and SARS-CoV-2 spike proteins did not alter NK cell activation in a K562 in vitro model. On the contrary, SARS-CoV-2 spike 1 protein (SP1) intracellular expression by lung epithelial cells resulted in NK cell-reduced degranulation. Further experiments revealed a concomitant induction of HLA-E expression on the surface of lung epithelial cells and the recognition of an SP1-derived HLA-E-binding peptide. Simultaneously, there was increased modulation of the inhibitory receptor NKG2A/CD94 on NK cells when SP1 was expressed in lung epithelial cells. We ruled out the GATA3 transcription factor as being responsible for HLA-E increased levels and HLA-E/NKG2A interaction as implicated in NK cell exhaustion. We show for the first time that NK cells are affected by SP1 expression in lung epithelial cells via HLA-E/NKG2A interaction. The resulting NK cells’ exhaustion might contribute to immunopathogenesis in SARS-CoV-2 infection.

Abstract 037: A Role for IL-17 to Activate Cytolytic Natural Killer Cells in Response to Placental Ischemia

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Denise C Cornelius ◽  
D'Andrea S Thomas ◽  
Jamil Elfarra ◽  
Taia R McAfee ◽  
Babbette LaMarca
Keyword(s):  
Blood Pressure ◽  
Nk Cells ◽  
Renal Dysfunction ◽  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Blood Pressure Response ◽  
Cell Phenotype ◽  
Uterine Perfusion ◽  
Placental Ischemia

Women with preeclampsia (PE), newly developed hypertension and renal dysfunction during pregnancy, have small-for-gestational-age babies and demonstrate an increase in the inflammatory cytokine IL-17, placental oxidative stress, and cytolytic natural killer (NK) cell activation. The stimulus of the cytolytic NK cell phenotype during PE is currently unknown. Moreover, the specific role of cytolytic NK cells in the pathophysiology of preeclampsia has not been clearly defined. The reduced uterine perfusion pressure (RUPP) model of placental ischemia exhibits many of the characteristics of preeclampsia including hypertension, renal dysfunction, chronic inflammation and intrauterine growth restriction (IUGR). In this study, we tested the hypothesis that placental ischemia results in cytolytic activation of NK cells, and examined a role for the increased IL-17, in response to placental ischemia, to activate cytolytic NK cells. In this study, blood pressure (MAP) and pup weight were measured, and PBMCs and placental lymphocytes were examined via flow cytometry for surface makers of cytolytic NK cell activation. MAP significantly increased in response to placental ischemia from 103±4.1 mmHg in NP (n=6) to 129.1±3.1 mmHg (n=8) in RUPP rats (p<0.001). Neutralization of IL-17 with a soluble receptor attenuated the blood pressure response to 106.3±2.3 mmHg in RUPP+IL-17RC rats (n=3). Pup weight is significantly decreased in RUPP rats (2.52±0.18g in NP vs 2.03±0.05g in RUPP (p<0.05)), which increased to 2.54±0.36g in RUPP+IL-17RC. Cytolytic activation of circulating NK cells was not significantly changed among any of the groups (NP: 2.49±1.1%; RUPP: 7.74±3.2%; RUPP+IL-17RC:5.50±2.8%). However, cytolytic activation of placental NK cells increased in response to placental ischemia (NP: 3.4±1.1% vs RUPP 10.0±3.4%), and was completely attenuated after treatment with the soluble IL-17 receptor (RUPP+IL-17RC: 0.33±0.17%). These results suggest a role for placental ischemia and increased IL-17 to stimulate cytolytic NK cells. Furthermore, this study links the IL-17 pathway with cytolytic NK cell activation and IUGR in response to placental ischemia, potentially identifying new therapeutic targets to improve maternal and fetal outcomes of PE.

scholarly journals p46, a Novel Natural Killer Cell–specific Surface Molecule That Mediates Cell Activation

1997 ◽  
Vol 186 (7) ◽  
pp. 1129-1136 ◽  
Author(s):  
Simona Sivori ◽  
Massimo Vitale ◽  
Luigia Morelli ◽  
Lorenza Sanseverino ◽  
Raffaella Augugliaro ◽  
...  
Keyword(s):  
Specific Surface ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Cytolytic Activity ◽  
Surface Molecule ◽  
Limited Information ◽  
Cell Clones

Limited information is available on the surface molecules that are involved in natural killer (NK) cell triggering. In this study, we selected the BAB281 monoclonal antibody (mAb) on the basis of its ability to trigger NK-mediated target cell lysis. BAB281 identified a novel NK cell–specific surface molecule of 46 kD (p46) that is expressed by all resting or activated NK cells. Importantly, unlike the NK cell antigens identified so far, the expression of p46 was strictly confined to NK cells. Upon mAb-mediated cross-linking, p46 molecules induced strong cell triggering leading to [Ca2+]i increases, lymphokine production, and cytolytic activity both in resting NK cells and NK cell clones. The p46-mediated induction of Ca2+ increases or triggering of cytolytic activity was downregulated by the simultaneous engagement of inhibitory receptors including p58, p70, and CD94/NKG2A. Both the unique cellular distribution and functional capability of p46 molecules suggest a possible role in the mechanisms of non-major histocompatibility complex–restricted cytolysis mediated by human NK cells.

scholarly journals Natural killer cell behavior in lymph nodes revealed by static and real-time imaging

2006 ◽  
Vol 203 (3) ◽  
pp. 619-631 ◽  
Author(s):  
Marc Bajénoff ◽  
Béatrice Breart ◽  
Alex Y.C. Huang ◽  
Hai Qi ◽  
Julie Cazareth ◽  
...  
Keyword(s):  
T Cell ◽  
Lymph Nodes ◽  
Nk Cells ◽  
Natural Killer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Leishmania Major ◽  
Nk Cell ◽  
Killer Cell

Natural killer (NK) cells promote dendritic cell (DC) maturation and influence T cell differentiation in vitro. To better understand the nature of the putative interactions among these cells in vivo during the early phases of an adaptive immune response, we have used immunohistochemical analysis and dynamic intravital imaging to study NK cell localization and behavior in lymph nodes (LNs) in the steady state and shortly after infection with Leishmania major. In the LNs of naive mice, NK cells reside in the medulla and the paracortex, where they closely associate with DCs. In contrast to T cells, intravital microscopy revealed that NK cells in the superficial regions of LNs were slowly motile and maintained their interactions with DCs over extended times in the presence or absence of immune-activating signals. L. major induced NK cells to secrete interferon-γ and to be recruited to the paracortex, where concomitant CD4 T cell activation occurred. Therefore, NK cells form a reactive but low mobile network in a strategic area of the LN where they can receive inflammatory signals, interact with DCs, and regulate colocalized T cell responses.

scholarly journals Natural Killer Anti-Tumor Activity Can Be Achieved by In Vitro Incubation With Heat-Killed BCG

2021 ◽  
Vol 12 ◽  
Author(s):  
Gloria Esteso ◽  
Nacho Aguiló ◽  
Esther Julián ◽  
Omodele Ashiru ◽  
Mei. M. Ho ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Myeloid Cell ◽  
Activation Effect ◽  
Aqueous Fraction ◽  
Cytokine Activation

Natural Killer cell receptors allow this heterogeneous immune population to efficiently fight both tumors and infection, so their use as immunotherapy agents is an active field of research. Cytokine activation, particularly by myeloid cell-derived IL15, can induce potent NK anti-tumor responses. While studying the mechanism of action of intravesical instillations of Bacille Calmette-Guérin (BCG) as therapy for patients with high risk non-muscle invasive bladder cancer, we showed that BCG can activate a cytotoxic CD56bright NK cell population which efficiently recognized bladder cancer cells. This pioneer immunotherapy provides an invaluable model to understand the role of different immune populations in tumor elimination. However, during the propagation of BCG worldwide a large number of genetically diverse BCG substrains developed. Here, we investigated the capacity of different BCG substrains to promote NK cell activation and confirmed that they were able to activate lymphocytes. Tice, Connaught and Moreau were the substrains with a stronger NK activation effect as measured by CD56 upregulation. Surprisingly, dead mycobacteria also stimulated PBMC cultures and we further demonstrate here that subcellular fractions of BCG-Tice, in the absence of live mycobacteria, could also induce an NK cell response. Lipids from BCG-Tice, but not from Mycobacterium bovis, stimulated NK cell activation and degranulation, whereas the aqueous fraction of either bacteria did not activate lymphocytes. However, delipidated BCG-Tice bacteria were able to activate effector cells (CD3+CD56+ and NK, CD3-CD56+). These data demonstrate that different components of mycobacteria can stimulate different immune subpopulations resulting in phenotypes suitable for cancer elimination.

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