Natural Killer T Cells Are Involved in Atherosclerotic Plaque Instability in Apolipoprotein-E Knockout Mice.

Yoshinori Ohmura,Naoki Ishimori,Hiroyuki Tsutsui,Shunpei Horii,Kazuya Iwabuchi,Satoshi Tokuhara,Takashi Yokota,Akimichi Saito

doi:10.3390/ijms222212451

Abstract

The infiltration and activation of macrophages as well as lymphocytes within atherosclerotic lesion contribute to the pathogenesis of plaque rupture. We have demonstrated that invariant natural killer T (iNKT) cells, a unique subset of T lymphocytes that recognize glycolipid antigens, play a crucial role in atherogenesis. However, it remained unclear whether iNKT cells are also involved in plaque instability. Apolipoprotein E (apoE) knockout mice were fed a standard diet (SD) or a high-fat diet (HFD) for 8 weeks. Moreover, the SD- and the HFD-fed mice were divided into two groups according to the intraperitoneal injection of α-galactosylceramide (αGC) that specifically activates iNKT cells or phosphate-buffered saline alone (PBS). ApoE/Jα18 double knockout mice, which lack iNKT cells, were also fed an SD or HFD. Plaque instability was assessed at the brachiocephalic artery by the histological analysis. In the HFD group, αGC significantly enhanced iNKT cell infiltration and exacerbated atherosclerotic plaque instability, whereas the depletion of iNKT cells attenuated plaque instability compared to PBS-treated mice. Real-time PCR analyses in the aortic tissues showed that αGC administration significantly increased expressional levels of inflammatory genes such as IFN-γ and MMP-2, while the depletion of iNKT cells attenuated these expression levels compared to those in the PBS-treated mice. Our findings suggested that iNKT cells are involved in the exacerbation of plaque instability via the activation of inflammatory cells and upregulation of MMP-2 in the vascular tissues.

Highlights

Clinical complications of atherosclerosis, such as myocardial infarction and ischemic stroke, result from the sudden thrombotic occlusion of the artery that arises from atherosclerotic plaques not necessarily causing flow-limiting stenoses [1]
We have demonstrated that invariant Natural killer T (NKT) cells, which are the major subset of NKT cells and possess a restricted TCR expression (Vα14-Jα18 in mice and Vα24-Jα18 in humans), are involved in atherogenesis, and their activation decreased collagen content and increased cellularity within the atherosclerotic lesions in apolipoprotein E knockout mice [5]
The present study demonstrated that the activation of invariant natural killer T (iNKT) cells by an administration of αGC exacerbated atherosclerotic plaque instability via activating macrophages and T

Summary

Introduction

Clinical complications of atherosclerosis, such as myocardial infarction and ischemic stroke, result from the sudden thrombotic occlusion of the artery that arises from atherosclerotic plaques not necessarily causing flow-limiting stenoses [1]. Physical disruption of the atherosclerotic plaque is attributable to rupture of the fibrous cap that overlies the lipid core with the plaque [2]. It has been reported that T lymphocyte activation markedly increases production of interferon (IFN)-γ and strongly inhibits the synthesis of collagens by vascular SMC. IFN-γ inhibits the proliferation of vascular SMCs, leading to instability of the plaque due to reduction of collagen-synthesizing cellular component in the plaque. It has been demonstrated that T lymphocytes in atherosclerotic plaques activate macrophages via increased expression of matrix metalloproteinase (MMP)-2 and MMP-9. T cells play an important role in regulation of SMCs and macrophages, both of which may restore the integrity of the fibrous cap of the plaque and prevent plaque rupture

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Results

Conclusion