CD1d deficiency inhibits the development of abdominal aortic aneurysms in LDL receptor deficient mice.

Vivian De Waard,Kim L L Habets,Saskia C De Jager,Michael Bader,Johan Kuiper,Ilze Bot,Louis Boon,Mariëtte N D Ter Borg,Puck Van Osch,Gijs H M Van Puijvelde,Rosemarie E Van Bochove,Mariska Vos,Amanda C Foks

doi:10.1371/journal.pone.0190962

Abstract

An abdominal aortic aneurysm (AAA) is a dilatation of the abdominal aorta leading to serious complications and mostly to death. AAA development is associated with an accumulation of inflammatory cells in the aorta including NKT cells. An important factor in promoting the recruitment of these inflammatory cells into tissues and thereby contributing to the development of AAA is angiotensin II (Ang II). We demonstrate that a deficiency in CD1d dependent NKT cells under hyperlipidemic conditions (LDLr-/-CD1d-/- mice) results in a strong decline in the severity of angiotensin II induced aneurysm formation when compared with LDLr-/- mice. In addition, we show that Ang II amplifies the activation of NKT cells both in vivo and in vitro. We also provide evidence that type I NKT cells contribute to AAA development by inducing the expression of matrix degrading enzymes in vSMCs and macrophages, and by cytokine dependently decreasing vSMC viability. Altogether, these data prove that CD1d-dependent NKT cells contribute to AAA development in the Ang II-mediated aneurysm model by enhancing aortic degradation, establishing that therapeutic applications which target NKT cells can be a successful way to prevent AAA development.

Highlights

According to the World Health Organization, cardiovascular diseases are the leading cause of death worldwide, responsible for 17.7 million deaths each year, with atherosclerosis, a chronic inflammation of the vessel wall, as the major cause
Inflammatory cells such as monocytes/macrophages, neutrophils, T cells, B cells, mast cells and NK cells infiltrate the vessel wall and locally secrete cytokines, chemokines and other inflammatory factors resulting in the progression of abdominal aortic aneurysm (AAA).[3, 10]
Both pro-inflammatory Th1 cells secreting IFN-γ and thereby increasing the MMP-2 and MMP-9 expression[11, 14] and anti-inflammatory Th2 cells secreting IL-4 and concomitantly increasing the expression of MMP-9 and MMP-12 seem to be involved in AAA development. [18, 39] Th1 cells are linked to protection against the formation of AAA, since blocking of IFN-γ signalling pathways induced AAA formation in allografted aortas.[18]

Summary

Introduction

According to the World Health Organization, cardiovascular diseases are the leading cause of death worldwide, responsible for 17.7 million deaths each year, with atherosclerosis, a chronic inflammation of the vessel wall, as the major cause. Another common vascular disorder, linked with aging and atherosclerosis, is the development of an abdominal aortic aneurysm (AAA) affecting 2–8% of the elderly people. AAA, a chronic inflammatory disease, is defined as a local permanent dilation of the abdominal part of the aorta transcending 1.5-times the normal aortic diameter.[1, 2] An AAA is often asymptomatic and undiagnosed until rupture of the aorta occurs.

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Conclusion