scholarly journals Disorder of natural killer cell functional activity in experimental stroke of different severity

2018 ◽  
pp. 124-127
Author(s):  
А.Е. Кульчиков
Keyword(s):  
Risk Factors ◽  
Experimental Study ◽  
Natural Killer Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Functional Activity ◽  
Wistar Rats ◽  
Killer Cell ◽  
Experimental Stroke ◽  
Acute Period

Актуальность. Изучение факторов риска развития инфекционно-воспалительных осложнений и путей их снижения при инсульте является актуальной неврологической проблемой. Цель: оценка функциональной активности клеток естественных киллеров в остром периоде экспериментального инсульта различной степени тяжести. Методы. В проведенном экспериментальном исследовании на животных (крысы линии Вистар, массой 200-220 г, n = 50) изучали функциональная активность естественных киллеров селезенки, при моделировании монополушарного левостороннего экспериментального инсульта (ЭИ) различной степени тяжести. Результаты. Показано, что у животных на 7-й день инсульта отмечается статистически значимое снижение функциональной активности естественных киллеров селезенки: ЭИ легкой степени - 20 (19; 23)%, р = 0,001, ЭИ средней степени - 19 (17; 21)%, р < 0,001, ЭИ тяжелой степени - 18 (16; 22)%, р < 0,001. Нарушения функциональной активности естественных киллеров более выражены на модели ЭИ средней и тяжёлой степени тяжести. Заключение. Показано, что при ЭИ наблюдается снижение функциональной активности естественных киллеров селезёнки, которое нарастает при увеличении степени тяжести инсульта. Background. Studying risk factors for development of infectious and inflammatory complications and ways to reduce them in stroke is a modern challenge to neurology. Aim: Evaluating the functional activity of natural killer (NK) cells in the acute period of experimental stroke (ES) of different severity. Methods. In this experimental study, the functional activity of spleen NK cells was studied in Wistar rats weighing 200-220 g (n = 50) with ES of different severity. Results. On the 7th day of stroke. the functional activity of spleen NK was significantly decreased: in mild ES, 20 (19; 23)%, р = 0.001, in moderate ES, 19 (17; 21)%, р <0.001, and in severe ES, (16; 22)%, р < 0.001. Disorders of the NK functional activity were more pronounced in moderate and severe ES. Conclusion. ES was associated with impaired functional activity of NK cells, which progressed with increasing grade of ES severity.

scholarly journals A research-driven approach to the identification of novel natural killer cell deficiencies affecting cytotoxic function

Blood ◽  
2020 ◽  
Vol 135 (9) ◽  
pp. 629-637
Author(s):  
Michael T. Lam ◽  
Emily M. Mace ◽  
Jordan S. Orange
Keyword(s):  
Natural Killer Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Development ◽  
Impact Testing ◽  
Primary Immune Deficiency ◽  
Cell Cytotoxicity ◽  
Nk Cell Cytotoxicity

Abstract Natural killer cell deficiencies (NKDs) are an emerging phenotypic subtype of primary immune deficiency. NK cells provide a defense against virally infected cells using a variety of cytotoxic mechanisms, and patients who have defective NK cell development or function can present with atypical, recurrent, or severe herpesviral infections. The current pipeline for investigating NKDs involves the acquisition and clinical assessment of patients with a suspected NKD followed by subsequent in silico, in vitro, and in vivo laboratory research. Evaluation involves initially quantifying NK cells and measuring NK cell cytotoxicity and expression of certain NK cell receptors involved in NK cell development and function. Subsequent studies using genomic methods to identify the potential causative variant are conducted along with variant impact testing to make genotype-phenotype connections. Identification of novel genes contributing to the NKD phenotype can also be facilitated by applying the expanding knowledge of NK cell biology. In this review, we discuss how NKDs that affect NK cell cytotoxicity can be approached in the clinic and laboratory for the discovery of novel gene variants.

Adrenergic β1- and β1+2-receptor blockade suppress the natural killer cell response to head-up tilt in humans

1997 ◽  
Vol 83 (5) ◽  
pp. 1492-1498 ◽  
Author(s):  
M. Klokker ◽  
N. H. Secher ◽  
P. Madsen ◽  
M. Pedersen ◽  
B. K. Pedersen
Keyword(s):  
Natural Killer Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Response ◽  
Nk Cell ◽  
Killer Cell ◽  
Saline Control ◽  
Receptor Blockade ◽  
Natural Killer Cell Response ◽  
Head Up Tilt

Klokker, M., N. H. Secher, P. Madsen, M. Pedersen, and B. K. Pedersen. Adrenergic β1- and β1+2-receptor blockade suppress the natural killer cell response to head-up tilt in humans. J. Appl. Physiol. 83(5): 1492–1498, 1997.—To evaluate stress-induced changes in blood leukocytes with emphasis on the natural killer (NK) cells, eight male volunteers were followed during three trials of head-up tilt with adrenergic β1- (metoprolol) and β1+2- (propranolol) blockade and with saline (control) infusions. The β1- and β1+2-receptor blockade did not affect the appearance of presyncopal symptoms, but the head-up tilt induced a transient lymphocytosis that was abolished by β1+2-receptor blockade but not by β1-receptor blockade. Head-up tilt also resulted in delayed neutrophilia, which was insensitive to β-receptor blockade. Lymphocyte subset analysis revealed that the head-up tilt resulted in a twofold increase in the percentage and absolute number of CD3−/CD16+and CD3−/CD56+NK cells in peripheral blood and that this increase was partially blocked by metoprolol and abolished by propranolol. The NK cell activity on a per NK cell basis did not change during head-up tilt, indicating that the cytotoxic capability of NK cells recruited to circulation is unchanged. The data suggest that the head-up tilt-induced lymphocytosis was due mainly to CD16+and CD56+NK cells and that their recruitment to the blood was inhibited by β1- and especially β1+2-receptor blockade. Thus stress-induced recruitment of lymphocytes, and of NK cells in particular, is mediated by epinephrine through activation of β-receptors on the lymphocytes.

Inhibition of human natural killer cell functional activity by human aspartyl β-hydroxylase

2014 ◽  
Vol 23 (2) ◽  
pp. 452-459 ◽  
Author(s):  
Ting Huyan ◽  
Qi Li ◽  
Lin-Jie Ye ◽  
Hui Yang ◽  
Xiao-Ping Xue ◽  
...  
Keyword(s):  
Natural Killer Cell ◽  
Natural Killer ◽  
Functional Activity ◽  
Killer Cell ◽  
Human Natural Killer Cell

scholarly journals Natural killer cells suppress human erythroid stem cell proliferation in vitro

Blood ◽  
1984 ◽  
Vol 63 (2) ◽  
pp. 260-269 ◽  
Author(s):  
KF Mangan ◽  
ME Hartnett ◽  
SA Matis ◽  
A Winkelstein ◽  
T Abo
Keyword(s):  
Stem Cell ◽  
Natural Killer Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Human Natural Killer Cell ◽  
Percoll Density Gradient Centrifugation

Abstract To determine the role of natural killer (NK) cells in the regulation of human erythropoiesis, we studied the effects of NK-enriched cell populations on the in vitro proliferation of erythroid stem cells at three different levels of maturation (day 14 blood BFU-E, day 5–6 marrow CFU-E, and day 10–12 marrow BFU-E). NK cells were enriched from blood by Percoll density gradient centrifugation and by fluorescence- activated cell sorting (FACS), using the human natural killer cell monoclonal antibody, HNK-1. The isolated enriched fractions were cocultured with autologous nonadherent marrow cells or blood null cells and erythropoietin in a methylcellulose erythroid culture system. Cells from low-density Percoll fractions (NK-enriched cells) were predominantly large granular lymphocytes with cytotoxic activity against K562 targets 6–10-fold greater than cells obtained from high- density Percoll fractions (NK-depleted cells). In coculture with marrow nonadherent cells (NA) at NK:NA ratios of 2:1, NK-enriched cells suppressed day 5–6 CFU-E to 62% (p less than 0.025) of controls, whereas NK-depleted cells slightly augmented CFU-E to 130% of controls (p greater than 0.05). In contrast, no suppression of day 10–12 marrow BFU-E was observed employing NK-enriched cells. The NK CFU-E suppressor effects were abolished by complement-mediated lysis of NK-enriched cells with the natural killer cell antibody, HNK-1. Highly purified HNK- 1+ cells separated by FACS suppressed marrow CFU-E to 34% (p less than 0.025) and marrow BFU-E to 41% (p less than 0.025) of controls. HNK- cells had no significant effect on either BFU-E or CFU-E growth. NK- enriched cells were poor stimulators of day 14 blood BFU-E in comparison to equal numbers of NK-depleted cells or T cells isolated by E-rosetting (p less than 0.01). Interferon boosting of NK-enriched cells abolished their suboptimal burst-promoting effects and augmented their CFU-E suppressor effects. These studies provide evidence for a potential regulatory role of NK cells in erythropoiesis. The NK suppressor effect is maximal at the level of the mature erythroid stem cell CFU-E. These findings may explain some hypoproliferative anemias that develop in certain NK cell-activated states.

Hemostatic Factors Contribute to Tumor Cell Metastatic Potential by a Mechanism Linked to Natural Killer Cell Function.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 690-690 ◽  
Author(s):  
Joseph S. Palumbo ◽  
Kathryn E. Talmage ◽  
Jessica V. Massari ◽  
Christine M. La Jeunesse ◽  
Matthew J. Flick ◽  
...  
Keyword(s):  
Natural Killer Cell ◽  
Tumor Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Platelet Activation ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Metastatic Potential ◽  
Natural Killer Cell Function

Abstract A linkage between hemostatic system components and tumor cell metastatic potential has been well established, but the underlying mechanism(s) by which various circulating and cell-associated coagulation factors and platelets promote tumor cell dissemination remains to be fully defined. One potential mechanism by which tumor cell-associated microthrombi might enhance metastatic potential is by interfering with the cytolytic elimination of tumor cell emboli by natural killer (NK) cells. In order to explore this hypothesis, we studied tumor dissemination in mice lacking either fibrinogen or Gαq, a G protein critical for platelet activation. Comparative studies of experimental lung metastasis in control and Gαq−/− mice showed that loss of platelet activation resulted in a two-orders-of-magnitude decrease in pulmonary metastatic foci formed by either Lewis lung carcinoma or B16 melanoma. The difference in metastatic success was not the result of differences in tumor growth rate, as tumors transplanted into the dorsal subcutis of Gαq−/− and wildtype animals grew at similar rates. Rather, tumor cell fate analyses using radiolabeled tumor cells showed that the survival of tumor cells within the lung was significantly improved in mice that retained platelet activation function relative to Gαq−/− mice with a profound platelet activation defect. In order to examine the potential interplay between platelet activation and natural killer cell function, we compared pulmonary tumor cell survival in cohorts of control and Gαq−/− mice immuno-depleted of NK cells with an anti-asialo GM1 antibody. Remarkably, platelet function was no longer a determinant of metastatic potential in mice lacking NK cells. Given that fibrin(ogen) is also an established determinant of metastatic success we explored whether the influence of this key hemostatic factor on tumor cell dissemination was also mechanistically-coupled to natural killer cell function. We interbred fibrinogen-deficient mice with Gz-Ly49A transgenic mice known to have a constitutive deficit in NK cells. In those cohorts of mice with normal NK cells, we affirmed the earlier finding that fibrinogen deficiency resulted in a significant diminution in metastatic potential. However, consistent with our findings in mice with defective platelet activation, fibrinogen was found to no longer be a determinant of metastatic potential in mice lacking NK cells. These data establish another important link between innate immune surveillance and the hemostatic system. Further, it appears that at least one mechanism by which tumor cell-associated microthrombi increase metastatic potential is by restricting NK cell-mediated tumor cell elimination. Given that NK cell cytotoxicity requires direct contact with any target cell, one attractive model presently being explored is that tumor cell-associated platelets physically block NK cell access to tumor cell emboli.

scholarly journals Enhancing both CT imaging and natural killer cell-mediated cancer cell killing by a GD2-targeting nanoconstruct

2016 ◽  
Vol 4 (3) ◽  
pp. 513-520 ◽  
Author(s):  
Peifu Jiao ◽  
Mario Otto ◽  
Qiaohong Geng ◽  
Chencan Li ◽  
Faming Li ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Natural Killer Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Computerized Tomography ◽  
Cancer Cell ◽  
Killer Cell ◽  
Melanoma Cells ◽  
Cell Killing ◽  
Ct Imaging

Novel gold nanoparticles specifically enhance computerized tomography (CT) imaging contrast and to stimulate the attacks on neuroblastoma and melanoma cells by natural killer (NK) cells.

scholarly journals Hepatic Niche Leads to Aggressive Natural Killer Cell Leukemia Proliferation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3309-3309
Author(s):  
Kazuaki Kameda ◽  
Yuji Miyatake ◽  
Yoshinobu Kanda ◽  
Ai Kotani
Keyword(s):  
Bone Marrow ◽  
Natural Killer Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Rna Sequencing ◽  
Research Funding ◽  
Killer Cell ◽  
Cell Leukemia

Abstract Aggressive natural killer cell leukemia (ANKL) is a rare form of natural killer (NK)-cell neoplasm with median survival of less than 2 months. Recently, the genomic mutation analysis using tumor cells reveled that the mutational profile of ANKL was similar to that of extranodal NK / T-cell lymphoma, which has relatively better prognosis than ANKL, explaining no causative mutations with a dismal prognosis. Here, using patient-derived xenograft model (PDX) mouse, we show that hepatic niche plays an important role in the ANKL biology. We established PDX mouse by intravenously injecting ANKL cells derived from patient peripheral blood or bone marrow samples to immunocompromised mice, which enables comprehensive analysis for tumor cells as well as tumor microenvironment. In total, we obtained four PDX strains derived from different patients. Time series pathological and flowcytometric analyses revealed that the ANKL cells initially engrafted and proliferated in sinusoidal or peri-portal area of the liver. This sinusoid or peri-portal distribution of ANKL in the liver was also confirmed with the patient liver specimen. To further determine the feature of ANKL in the liver, we selected liver or spleen tropic cells by serial adaptive transfer from each organ to the next mice. The liver-tropic ANKL cells proliferated more rapidly than splenic ANKL cells, which was evident by the significantly shorter survival of PDX mice injected liver-tropic cells (Figure). We performed RNA-sequencing using liver-tropic ANKL cells, spleen-tropic ANKL cells and NK-cells derived from healthy donors. These three types of cells showed distinct populations in principal component analysis. To further clarify the interaction between ANKL and liver niche, we performed additional RNA sequencing using total liver of mouse with or without bearing leukemic cells. In the cell-cell interaction analysis, we used two computational methods, mixed-species RNA-seq (Komura, et al. BMC Genomics 2016), which can distinguish transcripts derived from human (cancer) with mouse (non-cancer niche cells), and NicheNet (Browaeys, et al. Nat Methods 2020), which is a computational algorithm to model intercellular communication by linking ligands to target genes. These two methods allowed us to investigate the interaction between liver niche ligands and ANKL receptors. Among the listed ligand-receptor interactions, we focused on the macrophage migration inhibitory factor (MIF) and its receptor, CD74 axis. While CD74 was upregulated in ANKL cells compared with normal NK cells, MIF was highly expressed in the liver mainly liver sinusoid and Kupffer cells. Although we failed to culture primary ANKL cells in vitro, ANKL cells treated with MIF showed improved viability in vitro compared with untreated cells. Deletion of CD74 on the ANKL cells using CRISPR-Cas9 system attenuated the tumor formation in the liver as well as in bone marrow and spleen of PDX mouse compared with the wild type ANKL cells. These findings highlight that the liver, non-canonical hematopoietic organ in adults, is a principal niche where the liver specific components are required for survival and proliferation of ANKL cells. MIF-CD74 axis might play an important role in the communication between ANKL and hepatic niche. Figure 1 Figure 1. Disclosures Kanda: Otsuka Pharmaceutical: Honoraria, Research Funding; Sanofi: Research Funding; MSD: Honoraria.

scholarly journals Natural killer cell-derived exosomal miR-1249-3p attenuates insulin resistance and inflammation in mouse models of type 2 diabetes

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ying Wang ◽  
Mengwei Li ◽  
Lin Chen ◽  
Huan Bian ◽  
Xiangying Chen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Natural Killer Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Ternary Complex ◽  
Killer Cell ◽  
Enhance Insulin Sensitivity

AbstractNatural killer (NK) cells have been suggested to be associated with type 2 diabetes by regulating systemic inflammation. However, the mechanism by which NK cells regulate insulin sensitivity remains unknown. This study shows that NK-derived exosomes from lean mice attenuate obesity-induced insulin resistance and inflammation in mice of type 2 diabetes. Moreover, lean NK-derived exosomes enhance insulin sensitivity and relieve inflammation in adipocytes and hepatocytes. MiR-1249-3p, which is significantly upregulated in lean NK-derived exosomes, can be transferred from NK cells to adipocytes and hepatocytes via exosomes. NK-derived exosomal miR-1249-3p dramatically induces cellular insulin sensitivity and relieves inflammation. Mechanistically, exosomal miR-1249-3p directly targets SKOR1 to regulate the formation of ternary complex SMAD6/MYD88/SMURF1, which mediates glucose homeostasis by suppressing the TLR4/NF-κB signaling pathway. This study reveals an emerging role for NK-derived exosomal miR-1249-3p in remission of insulin resistance, and provides a series of potential therapeutic targets in type 2 diabetes.

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