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            Natural Killer T Cells Potently Augment Aortic Root Atherosclerosis by Perforin- and Granzyme B-Dependent Cytotoxicity

Li, Yang; To, Karen; Kanellakis, Peter; Hosseini, Hamid; Deswaerte, Virginie; Tipping, Peter G.; Smyth, Mark J.; Toh, Ban‐Hock; Bobik, Alexander; Kyaw, Tin

doi:10.1161/circresaha.116.304734

Cited by 53 publications

(41 citation statements)

References 75 publications

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“…Increased inflammatory cell infiltrate containing macrophages and T-cells positively correlates with plaque size and instability [17]. Macrophages have been extensively studied in atherosclerosis, with increasing evidence also pointing to a role for T-cells in mediating pro-inflammatory and atherogenic responses in the aortic sinus [18,19]. Moreover, hyperglycaemia has been shown to induce activation of human T-cells [20] and increase T-cell infiltration into the atherosclerotic aorta of diabetic ApoE −/− mice [21].…”

Section: Introductionmentioning

confidence: 99%

Differential effects of NOX4 and NOX1 on immune cell-mediated inflammation in the aortic sinus of diabetic ApoE−/− mice

et al. 2016

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Oxidative stress and inflammation are central mediators of atherosclerosis particularly in the context of diabetes. The potential interactions between the major producers of vascular reactive oxygen species (ROS), NADPH oxidase (NOX) enzymes and immune-inflammatory processes remain to be fully elucidated. In the present study we investigated the roles of the NADPH oxidase subunit isoforms, NOX4 and NOX1, in immune cell activation and recruitment to the aortic sinus atherosclerotic plaque in diabetic ApoE(-/-) mice. Plaque area analysis showed that NOX4- and NOX1-derived ROS contribute to atherosclerosis in the aortic sinus following 10 weeks of diabetes. Immunohistochemical staining of the plaques revealed that NOX4-derived ROS regulate T-cell recruitment. In addition, NOX4-deficient mice showed a reduction in activated CD4(+) T-cells in the draining lymph nodes of the aortic sinus coupled with reduced pro-inflammatory gene expression in the aortic sinus. Conversely, NOX1-derived ROS appeared to play a more important role in macrophage accumulation. These findings demonstrate distinct roles for NOX4 and NOX1 in immune-inflammatory responses that drive atherosclerosis in the aortic sinus of diabetic mice.

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Section: Introductionmentioning

confidence: 99%

Differential effects of NOX4 and NOX1 on immune cell-mediated inflammation in the aortic sinus of diabetic ApoE−/− mice

et al. 2016

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“…Inflammatory conditions such as hyperlipidemia induce the upregulation of adhesion molecules (including ICAM-1) on endothelial cells, which leads to the accumulation of leukocytes at the site of endothelial activation. iNKT cells have been shown to aggravate atherosclerosis (18, 42-49), but the precise mechanism by which they induce their pro-atherosclerotic effects—plaque growth, induction of apoptosis, promotion of angiogenesis—have not been fully elucidated. It is clear that arterial lesions typically include both CD1d + APCs and iNKT cells (13-17).…”

Section: Discussionmentioning

confidence: 99%

“…It is clear that arterial lesions typically include both CD1d + APCs and iNKT cells (13-17). iNKT cells isolated from human atherosclerotic plaques appear to induce apoptosis of smooth muscle cells, potentially through IFNγ-induced upregulation of FAS or through the secretion of the lytic proteins granzyme and perforin B (15, 49). Additionally, iNKT cells have been shown to secrete IL-8 when activated, which has been shown to promote angiogenesis, a feature of unstable atherosclerotic plaques (17).…”

Section: Discussionmentioning

confidence: 99%

Human Invariant NKT Cells Induce IL-1β Secretion by Peripheral Blood Monocytes via a P2X7-Independent Pathway

Felley

Sharma

Theisen

et al. 2016

The Journal of Immunology

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The cytokine IL-1β plays a central role in inflammatory responses that are initiated by microbial challenges, as well as in those that are due to endogenous processes (often called “sterile” inflammation). IL-1β secretion that occurs independently of microbial stimulation is typically associated with the presence of endogenous alarmins, such as extracellular ATP (an indicator of cytopathic damage). Here we show that IL-2 activated human iNKT cells stimulate the secretion of IL-1β protein by human peripheral blood monocytes in a manner that requires neither the presence of microbial compounds nor signaling through the extracellular ATP receptor P2X7. Monocyte IL-1β production was specifically induced by iNKT cells, since similarly activated polyclonal autologous T cells did not have this effect. Secretion of IL-1β protein occurred rapidly (within 3-4 hours), and required cell contact between the iNKT cells and monocytes. Similar to IL-1β production induced by TLR stimulation, the iNKT-induced pathway appeared to entail a two-step process involving NFκB signaling and IL1B gene transcription, as well as assembly of the NLRP3 inflammasome and activation of caspase 1. However, in contrast to the classical inflammasome-mediated pathway of IL-1β production, activation of monocytes via P2X7 was dispensable for iNKT-induced IL-1β secretion and potassium efflux was not required. Moreover, the iNKT-induced effect involved caspase 8 activity, yet induced little monocyte death. These results suggest that IL-2 activated human iNKT cells induce monocytes to produce IL-1β through a distinctive pathway that does not require the presence of microbial danger signals or alarmins associated with cytopathic damage.

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“…96 Natural killer T (NKT) cells, which bridge the gap between innate and adaptive immunity, accumulate in human rupture-prone shoulder regions of vulnerable plaques, together with dendritic cells. 97 In ApoE −/− mice, Li et al 98 showed that NKT cells, in particular CD4 + NKT cells, exert their effects on atherosclerotic lesions via cytotoxic mechanisms, mostly via perforin and granzyme B, stimulating apoptosis and large increases in necrotic cores. NKT cells are activated by many mechanisms, including lipid antigen presentation via CD1d expressed by dendritic cells, 99 which may explain their colocalization in lesions, 97 or via IgG antibodies activating NKT cell Fcgamma RIII 100 ; IgG auto-antibodies can be active mediators of atherosclerotic plaque instability.…”

Section: Emerging Role Of Lymphocytes In Plaque Instabilitymentioning

confidence: 99%

Atherosclerotic Plaque Rupture

Chen

Huang

Kyaw

et al. 2016

ATVB

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CD4 ⁺ Natural Killer T Cells Potently Augment Aortic Root Atherosclerosis by Perforin- and Granzyme B-Dependent Cytotoxicity

Abstract: Rag2−/− mice augmented aortic root atherosclerosis by ≈75% that was ≈30% of lesions in ApoE

Cited by 53 publications

References 75 publications

Differential effects of NOX4 and NOX1 on immune cell-mediated inflammation in the aortic sinus of diabetic ApoE−/− mice

Differential effects of NOX4 and NOX1 on immune cell-mediated inflammation in the aortic sinus of diabetic ApoE−/− mice

Human Invariant NKT Cells Induce IL-1β Secretion by Peripheral Blood Monocytes via a P2X7-Independent Pathway

Atherosclerotic Plaque Rupture

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CD4 + Natural Killer T Cells Potently Augment Aortic Root Atherosclerosis by Perforin- and Granzyme B-Dependent Cytotoxicity

Abstract: Rag2−/− mice augmented aortic root atherosclerosis by ≈75% that was ≈30% of lesions in ApoE

Cited by 53 publications

References 75 publications

Differential effects of NOX4 and NOX1 on immune cell-mediated inflammation in the aortic sinus of diabetic ApoE−/− mice

Differential effects of NOX4 and NOX1 on immune cell-mediated inflammation in the aortic sinus of diabetic ApoE−/− mice

Human Invariant NKT Cells Induce IL-1β Secretion by Peripheral Blood Monocytes via a P2X7-Independent Pathway

Atherosclerotic Plaque Rupture

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Product

Resources

About

CD4 ⁺ Natural Killer T Cells Potently Augment Aortic Root Atherosclerosis by Perforin- and Granzyme B-Dependent Cytotoxicity