Activation of invariant natural killer T cells ameliorates doxorubicin-induced cardiotoxicity in mice

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Y Obata ◽  
N Ishimori ◽  
A Saito ◽  
S Kinugawa ◽  
I Nakano ◽  
...  
Keyword(s):  
Body Weight ◽  
Natural Killer ◽  
Heart Tissue ◽  
M2 Macrophage ◽  
Funding Source ◽  
Inkt Cells ◽  
Arginase 1 ◽  
Relative Ratio ◽  
Invariant Natural Killer ◽  
Natural Killer T

Abstract Objective Doxorubicin (DOX) is one of the most important anticancer agents and widely used to treat cancers but clinical utility of DOX is limited for its dose-dependent cardiotoxicity. The precise mechanism of DOX-induced cardiotoxicity is still not fully understood but it has been reported that cardiac inflammation is involved in the cardiotoxicity. Invariant natural killer T (iNKT) cells, a unique subset of T lymphocytes that recognize glycolipid antigens and secrete a large amount of both Th1 and Th2 cytokines on activation, have been shown to play crucial roles in the regulation of immune responses. However, it remains unclear whether iNKT cells are involved in DOX-induced cardiotoxicity. Methods and results Male C57BL/6J mice were administered DOX (20mg/kg body weight; n=28) or vehicle (Vehicle; n=6). DOX-administered mice were further divided into 2 groups; those treated with α-galactosylceramide (αGC, 0.1μg/g body weight; DOX-αGC; n=14), which specifically activates iNKT cells, or those treated with PBS (DOX-PBS; n=14) by intraperitoneal injections (twice; 4 days before and 3 days after DOX administration).An echocardiography conducted at 14 days after DOX/Vehicle administration revealed that LV fractional shortening was significantly reduced in the DOX-PBS compared to the Vehicle (49.3±0.8% vs. 59.2±1.7%, P<0.05), and this decrease was completely attenuated in the DOX-αGC (57.7±1.3%, P<0.05 vs. DOX-PBS)without affecting LV end-diastolic diameter. Flow cytometric analysis revealed that the ratio of iNKT cells to mononuclear cells infiltrated into the heart tissue was significantly increased in the DOX+αGC compared to the Vehicle and the DOX+PBS (1.00±0.09% vs. 0.54±0.09% and 0.71±0.07%, P<0.05). Immuno-histochemistry revealed that the infiltration number of Iba1+macrophages in the heart tissue was significantly elevated in the DOX+αGC compared to the Vehicle and the DOX+PBS (55.4±3.2 cells/mm2 vs. 21.7±2.0 cells/mm2 and 37.5±5.9 cells/mm2, P<0.05) The ratio of fibrosis area to the heart tissue was markedly higher in the DOX-PBS than in Vehicle (4.3±0.5% vs. 2.2±0.1%, P<0.05), and this increase was completely attenuated in the DOX-αGC (2.8±0.1%, P<0.05 vs.DOX-PBS).Real-time PCR analysis revealed that mRNA expressions of M2 macrophage markers (Arginase 1 and Retnla) and IL-4 were significantly enhanced in the DOX+αGC compared to the DOX+PBS (Arginase 1: 2.5±0.4 vs. 1.6±0.3 [relative ratio to the Vehicle], P=0.08; Retnla: 2.4±0.5 vs. 1.1±0.2 [relative ratio to the Vehicle], P<0.05; IL-4: 1.0±0.3 vs. 8.94±2.8 [relative ratio to the DOX+PBS], P<0.05), while those of M1 macrophage markers (iNOS and MCP-1) did not change among all groups. Conclusions Activation of iNKT cells ameliorates DOX-induced cardiotoxicity in mice via enhanced M2 macrophage polarization with the upregulation of IL-4 and reducing cardiac fibrosis. iNKT cell activation can be a novel preventive strategy against DOX-induced cardiotoxicity. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Japan Agency for Medical Research and Development (18lm0203001j0002) and JSPS KAKENHI (18K15834).

scholarly journals Activation of Invariant Natural Killer T Cells by α-Galactosylceramide Attenuates the Development of Angiotensin II-Mediated Abdominal Aortic Aneurysm in Obese ob/ob Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Akimichi Saito ◽  
Naoki Ishimori ◽  
Satoshi Tokuhara ◽  
Tsuneaki Homma ◽  
Mikito Nishikawa ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
T Lymphocytes ◽  
Aortic Aneurysm ◽  
Natural Killer ◽  
M2 Macrophage ◽  
Inkt Cells ◽  
Abdominal Aortic ◽  
Invariant Natural Killer ◽  
Natural Killer T

The infiltration and activation of macrophages as well as lymphocytes within the aorta contribute to the pathogenesis of abdominal aortic aneurysm (AAA). Invariant natural killer T (iNKT) cells are unique subset of T lymphocytes and have a crucial role in atherogenesis. However, it remains unclear whether iNKT cells also impact on the development of AAA. Ob/ob mice were administered angiotensin II (AngII, 1,000 ng/kg/min) or phosphate-buffered saline (PBS) by osmotic minipumps for 4 weeks and further divided into 2 groups; α-galactosylceramide (αGC; PBS-αGC; n = 5 and AngII-αGC; n = 12), which specifically activates iNKT cells, and PBS (PBS-PBS; n = 10, and AngII-PBS; n = 6). Maximal abdominal aortic diameter was comparable between PBS-PBS and PBS-αGC, and was significantly greater in AngII-PBS than in PBS-PBS. This increase was significantly attenuated in AngII-αGC without affecting blood pressure. αGC significantly enhanced iNKT cell infiltration compared to PBS-PBS. The ratio of F4/80-positive macrophages or CD3-positive T lymphocytes area to the lesion area was significantly higher in AngII-PBS than in PBS-PBS, and was significantly decreased in AngII-αGC. Gene expression of M2-macrophage specific markers, arginase-1 and resistin-like molecule alpha, was significantly greater in aortic tissues from AngII-αGC compared to AngII-PBS 1 week after AngII administration, and this increase was diminished at 4 weeks. Activation of iNKT cells by αGC can attenuate AngII-mediated AAA in ob/ob mice via inducing anti-inflammatory M2 polarized state. Activation of iNKT cells by the bioactive lipid αGC may be a novel therapeutic target against the development of AAA.

P1623Activation of invariant natural killer T cells by alpha-galactosylceramide ameliorates doxorubicin-induced cardiotoxicity in mice

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
Y Obata ◽  
N Ishimori ◽  
A Saito ◽  
S Kinugawa ◽  
I Nakano ◽  
...  
Keyword(s):  
Body Weight ◽  
Natural Killer ◽  
Intraperitoneal Injection ◽  
Antineoplastic Agent ◽  
Left Ventricular ◽  
Dependent Manner ◽  
Inkt Cells ◽  
Anti Inflammatory ◽  
Invariant Natural Killer ◽  
Natural Killer T

Abstract Objective Doxorubicin (DOX) is an effective antineoplastic agent commonly used to treat many types of cancer but its clinical use is limited because of cardiotoxicity, which might proceed to irreversible cardiac dysfunction in a dose-dependent manner. The precise mechanism of DOX-induced cardiotoxicity is still not fully elucidated but it has been reported that cardiac inflammation is involved in the cardiotoxicity. Invariant natural killer T (iNKT) cells, a unique subset of T lymphocytes that recognize glycolipid antigens and secrete a large amount of Th1 and Th2 cytokines on activation, have been shown to play crucial roles in the regulation of immune responses. However, it remains unclear whether iNKT cells are involved in DOX-induced cardiotoxicity. Methods and results Male C57BL/6J mice were administered DOX (20mg/kg body weight single intraperitoneal injection; n=28) or vehicle (Vehicle; n=6). DOX-administered mice were further divided into 2 groups; α-galactosylceramide (αGC, 0.1μg/g body weight twice intraperitoneal injection; DOX-αGC; n=14), which specifically activates iNKT cells, or phosphate-buffered saline alone (PBS; DOX-PBS; n=14) 4 days before and 3 days after DOX administration. Survival rate at 14 days after DOX/Vehicle administration was significantly lower in DOX-PBS than in Vehicle (71% vs. 100%, P<0.05), and this decrease was completely attenuated in DOX-αGC (100%, P<0.05 vs. DOX-PBS). Echocardiography at 14 days after DOX/Vehicle administration revealed that left ventricular (LV) fractional shortening was significantly reduced in DOX-PBS compared to Vehicle (49.3±0.8% vs. 59.2±1.7%, P<0.05), and this decrease was completely attenuated in DOX-αGC (57.7±1.3%, P<0.05 vs. DOX-PBS) without affecting LV end-diastolic diameter. Picro-sirius red staining revealed that the ratio of fibrosis area to the cardiac tissue was markedly higher in DOX-PBS than in Vehicle (4.3±0.5% vs. 2.2±0.1%, P<0.05), and this increase was completely attenuated in DOX-αGC (2.8±0.1%, P<0.05 vs. DOX-PBS). Real-time PCR analysis revealed that mRNA expression of anti-inflammatory Th2 cytokine IL-4 was enhanced by 7.9-folds in DOX-αGC compared to DOX-PBS, though the difference did not reach statistically significance (P=0.09). Conclusions Activation of iNKT cells by αGC ameliorates DOX-induced cardiotoxicity in mice via up-regulation of anti-inflammatory IL-4 and reducing cardiac fibrosis. iNKT cell activation may be a novel therapeutic strategy against DOX-induced cardiotoxicity. Acknowledgement/Funding Japan Agency for Medical Research and Development (18lm0203001j0002) and JSPS KAKENHI (18K15834)

Abstract 11982: Circulating Invariant Natural Killer T Cells are Decreased in Patients With Chronic Heart Failure

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Akimichi Saito ◽  
Naoki Ishimori ◽  
Mikito Nishikawa ◽  
Shintaro Kinugawa ◽  
Hiroyuki Tsutsui
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Ejection Fraction ◽  
Natural Killer ◽  
Left Ventricular ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Inkt Cells ◽  
Lv Ejection Fraction ◽  
Invariant Natural Killer ◽  
Natural Killer T

Objective: Inflammatory mediators play a crucial role in the development of chronic heart failure (HF). Invariant natural killer T (iNKT) cells, a unique subset of T lymphocytes, which recognize glycolipid antigens and secrete a large amount of T helper (Th) 1/Th2 cytokines on activation, function as immunomodulatory cells in the various pathological processes. We have demonstrated that iNKT cells have a protective role against the development of left ventricular (LV) remodeling and failure after myocardial infarction in mice. However, it remains unclear whether iNKT cells are involved in the development of HF in humans. Methods and Results: Nine HF patients (NYHA II or III, LV ejection fraction 26.3±3.0%) and 8 healthy controls were studied. The mean age and male gender were comparable between HF and controls (51.2±5.1 vs. 45.1±4.5 years and 77.8 vs. 75.0%). The causes of HF were idiopathic dilated cardiomyopathy in 3, ischemic in 2, and others in 4 patients. Plasma BNP was significantly higher in HF than in controls (739.4±207.2 vs. 19.8±6.5 pg/mL, P <0.01). The number of circulating iNKT cells, identified by the positive-staining of Vα24-Jα18 T Cell Receptor by flow-cytometric analysis, was significantly lower in HF (747±85 vs. 1058±271 counts/mL, P <0.01). Its ratio to the total lymphocyte was also significantly lower (0.111±0.004 vs. 0.146±0.035%, P <0.01). Plasma interleukin-6 and high-sensitivity CRP were significantly higher in HF (3.99±0.86 vs. 0.78±0.14 pg/mL and 0.28±0.10 vs. 0.06±0.02 mg/dL, respectively, both P <0.01). LV ejection fraction ( r =0.72, P <0.05) and plasma log BNP ( r =-0.70, P <0.05) were significantly correlated to the ratio of iNKT cells among HF patients. Conclusions: Circulating iNKT cells were decreased in HF patients, suggesting that they have a potential role in the development of human HF.

Evaluating The Frequency Of Invariant Natural Killer T (iNKT) Cells In Nasal Polyps

2008 ◽  
Vol 121 (2) ◽  
pp. S263-S263
Author(s):  
M FEREIDOUNI ◽  
R FARIDHOSSEINI ◽  
M MAHMOUDI ◽  
M BAKHSHAEI ◽  
L ALHARTHI
Keyword(s):  
Natural Killer ◽  
Nasal Polyps ◽  
Inkt Cells ◽  
Invariant Natural Killer ◽  
Natural Killer T

scholarly journals Invariant natural killer T cells are functionally impaired in patients with systemic sclerosis

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Ann-Christin Pecher ◽  
Felix Kettemann ◽  
Elisa Asteriti ◽  
Hannes Schmid ◽  
Silke Duerr-Stoerzer ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Natural Killer ◽  
Immunosuppressive Drugs ◽  
Healthy Controls ◽  
Inkt Cells ◽  
Novel Approach ◽  
Functionally Impaired ◽  
Transfer Strategies ◽  
Invariant Natural Killer ◽  
Natural Killer T

Abstract Background Systemic sclerosis (SSc) is a potentially fatal autoimmune disease that leads to extensive fibrosis of the skin and internal organs. Invariant natural killer T (iNKT) cells are potent immunoregulatory T lymphocytes being able to orchestrate dysregulated immune responses. The purpose of this study was to evaluate numbers and function of iNKT cells in patients with SSc and to analyze their correlation with disease parameters. Methods Human iNKT cells from 88 patients with SSc and 33 healthy controls were analyzed by flow cytometry. Their proliferative capacity and cytokine production were investigated following activation with CD1d ligand α-galactosylceramide (α-GalCer). Results We observed an absolute and relative decrease of iNKT cells in patients with SSc compared with healthy controls. Interestingly, the subtype of SSc, disease severity, or treatment with immunosuppressive drugs did not affect iNKT cell numbers. However, T helper (Th) cell immune polarization was biased towards a Th17 immunophenotype in SSc patients. Moreover, iNKT cells from patients with SSc showed a significantly decreased expansion capacity upon stimulation with α-GalCer. Conclusion iNKT cells are deficient and functionally impaired in patients with SSc. Therefore, adoptive transfer strategies using culture-expanded iNKT cells could be a novel approach to treat SSc patients.

scholarly journals Vitamin D, invariant natural killer T-cells and experimental autoimmune disease

2011 ◽  
Vol 71 (1) ◽  
pp. 62-66 ◽  
Author(s):  
Margherita T. Cantorna ◽  
Jun Zhao ◽  
Linlin Yang
Keyword(s):  
Multiple Sclerosis ◽  
Vitamin D ◽  
Immune System ◽  
Vitamin D Deficiency ◽  
Natural Killer ◽  
Active Form ◽  
Inkt Cells ◽  
Invariant Natural Killer ◽  
Experimental Autoimmune ◽  
Natural Killer T

Vitamin D is an important regulator of the immune system in general and multiple sclerosis in particular. Experimentally (i), invariant natural killer T (iNKT) cells have been shown to be important suppressors of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE; an animal model of multiple sclerosis). Conversely, in experimental allergic asthma iNKT cells are required for disease induction and are therefore pathogenic. The active form of vitamin D (calcitriol) suppresses EAE. The development of EAE symptoms is accelerated in vitamin D deficiency. Interestingly experimental asthma is less severe in vitamin D deficiency although there is no effect of calcitriol on disease severity. The data suggest that an important target of vitamin D in EAE and asthma are the iNKT cells. Vitamin D and/or vitamin D receptor deficiency results in the impaired development of iNKT cells. Vitamin D is critical very early during development of the immune system. Low levels of vitamin D in utero resulted in significantly reduced numbers of iNKT cells that failed to recover when calcitriol was used to supplement neonatal or adult mice. The data suggest that one of the consequences of early vitamin D deficiency is a reduction in the numbers of iNKT cells that develop. The iNKT cells are required for the beneficial effects of calcitriol in EAE. The important role of vitamin D on iNKT cells could impact the development of human immune-mediated diseases including multiple sclerosis and asthma.

Relevance of sexual dimorphism to regulatory T cells: estradiol promotes IFN-γ production by invariant natural killer T cells

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2415-2420 ◽  
Author(s):  
Pierre Gourdy ◽  
Luiza M. Araujo ◽  
Ren Zhu ◽  
Barbara Garmy-Susini ◽  
Séverine Diem ◽  
...  
Keyword(s):  
T Cells ◽  
Natural Killer ◽  
Interleukin 4 ◽  
Response To Treatment ◽  
Inkt Cells ◽  
Gender Dimorphism ◽  
Ifn Γ ◽  
Invariant Natural Killer ◽  
Natural Killer T

Abstract Mechanisms accounting for gender dimorphism during immune responses are still poorly understood. Since invariant natural killer T (iNKT) cells exert important regulatory functions through their capacity to produce both T helper 1 (Th1) and Th2 cytokines, we addressed the question of whether these activities could be modulated by sexual hormones. We found that in vivo challenge with the specific ligand of iNKT cells, α-galactosylceramide (α-GalCer), induced significantly higher concentrations of interferon γ (IFN-γ) in the serum of female than in that of male mice, while interleukin 4 (IL-4) production was not modified. In support of a crucial role of ovarian hormones in this phenomenon, a significant decrease of serum IFN-γ concentrations occurred in ovariectomized females, in response to treatment with α-GalCer, while orchidectomy affected neither IFN-γ nor IL-4 serum concentrations in males. The implication of estrogens in this selective enhancement of IFN-γ production by iNKT cells was demonstrated by (1) the increased α-GalCer–induced IFN-γ synthesis by iNKT cells upon both in vitro and in vivo exposure to estradiol and (2) the abolition of the sex-linked difference in α-GalCer–induced IFN-γ release in estrogen receptor α-deficient mice. These results provide the first evidence that estrogens influence iNKT cells leading to this gender dimorphism in their cytokine production profile.

scholarly journals Distinct bioenergetic features of human invariant natural killer T (iNKT) cells enable retained functions in nutrient-deprived states

2021 ◽  
Author(s):  
Priya Khurana ◽  
Chakkapong Burudpakdee ◽  
Stephan A. Grupp ◽  
Ulf H. Beier ◽  
David M. Barrett ◽  
...  
Keyword(s):  
Natural Killer ◽  
Metabolic Flux ◽  
Cytokine Production ◽  
Inkt Cell ◽  
Flux Analysis ◽  
Inkt Cells ◽  
Effector Functions ◽  
Functional Features ◽  
Invariant Natural Killer ◽  
Natural Killer T

ABSTRACTInvariant natural killer T (iNKT) cells comprise a unique subset of lymphocytes that are primed for activation and possess innate NK-like functional features. Currently, iNKT cell-based immunotherapies remain in early clinical stages, and little is known about the ability of these cells to survive and retain effector functions within the solid tumor microenvironment (TME) long-term. In conventional T cells (TCONV), cellular metabolism is linked to effector functions and their ability to adapt to the nutrient-poor TME. In contrast, the bioenergetic requirements of iNKT cells – particularly those of human iNKT cells – at baseline and upon stimulation are not well understood; neither is how these requirements affect cytokine production or anti-tumor effector functions. We find that unlike TCONV, human iNKT cells are not dependent upon glucose or glutamine for cytokine production and cytotoxicity upon stimulation with anti-CD3 and anti-CD28. Additionally, transcriptional profiling revealed that stimulated human iNKT cells are less glycolytic than TCONV and display higher expression of fatty acid oxidation (FAO) and adenosine monophosphate-activated protein kinase (AMPK) pathway genes. Furthermore, stimulated iNKT cells displayed higher mitochondrial mass and membrane potential relative to TCONV. Real-time Seahorse metabolic flux analysis revealed that stimulated human iNKT cells utilize fatty acids as substrates for oxidation more than stimulated TCONV. Together, our data suggest that human iNKT cells possess different bioenergetic requirements from TCONV and display a more memory-like metabolic program relative to effector TCONV. Importantly, iNKT cell-based immunotherapeutic strategies could co-opt such unique features of iNKT cells to improve their efficacy and longevity of anti-tumor responses.

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