The paradoxical role of IL-17 in atherosclerosis

doi:10.1016/j.cellimm.2015.05.007

Cellular Immunology

Volume 297, Issue 1, September 2015, Pages 33-39

https://doi.org/10.1016/j.cellimm.2015.05.007 Get rights and content

Highlights

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IL-17 can have both protective and exacerbating effect on atherosclerosis.
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Various IL-17⁺ cells are pivotal to explore the role of IL-17 in atherosclerosis.
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IL-17 inhibitors should be used with caution to avoid aggravating atherosclerosis.

Abstract

Atherosclerosis is a chronic inflammatory disease mediated by innate and adaptive immune responses. In recent years, CD4⁺ T cells (Th1, Th2, Treg, and Th17) have been increasingly studied for their role in atherosclerosis pathophysiology, atheroma stability, plaque rupture, and life-threatening acute coronary syndrome. IL-17, a marker cytokine of Th17 cells, has been reported to be involved in the pathogenesis of rheumatoid arthritis, inflammatory bowel disease, and asthma. However, its role in atherosclerosis has been poorly characterized. This article provides a comprehensive overview of the role of IL-17 in the development of atherosclerosis and human coronary artery diseases.

Introduction

Cardiovascular disease is the leading cause of death around the world. Atherosclerosis is the primary cause of cardiovascular disease development and is driven by the inflammation of the arterial wall in response to a variety of pro-atherogenic stimuli such as modified low density lipoprotein (LDL) [1], [2]. Both innate and adaptive immune responses are involved in the pathogenesis of atherosclerosis [3]. Individuals with autoimmune diseases, such as rheumatoid arthritis, psoriasis, and systemic lupus erythematosus, show increased incidence of atherosclerosis [4], [5], [6]. This finding has increased research interest for investigating the role of adaptive immune responses in atherosclerosis. The role of adaptive immune cells has been particularly investigated and the findings revealed that T cells and other mediators of adaptive immunity are prevalent in atherosclerotic plaques [7]. Previous studies demonstrated that the T cells infiltrate arterial intima before the migration of monocytes and smooth muscle cells (SMC) into the intima during atherosclerotic progression [8], [9]. Of the several subsets of CD4⁺ T cells, Th17 cells have received increasing research interest. Th17 cells secrete IL-17, which has been shown to promote atherosclerotic progression through several pathways. Previous studies also indicate that IL-17 may serve as a link between the innate and adaptive immune system during atherosclerosis and mediate plaque lesion formation. However, contradictory findings indicating the anti-atherogenic role of IL-17 have also been reported. Thus, a complex and contradictory role has emerged for IL-17 in atherosclerosis. In this review, we describe the various roles of IL-17 in mediating atherosclerosis pathophysiology and outline the potential molecular mechanisms involved.

Section snippets

IL-17 family

The IL-17 family of cytokines includes six structurally related isoforms: IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F. All members of the IL-17 family share a similar protein structure characterized by four highly conserved cysteine residues [10]. IL-17A and IL-17F can form IL-17A and IL-17F homodimers as well as IL-17A/IL-17F heterodimers [11]. IL-17F has the highest degree of homology with IL-17A and exerts similar effects at a lower level. IL-17A and IL-17F have been reported to exist

The cellular sources of IL-17

IL-17 is produced by several cells, including Th17 cells, γδT cells, neutrophils, monocytes, and NK cells [16]. IL-17⁺ cells perform individual and synergistic roles to initiate complex cellular networks.

The paradoxical role of IL-17 in atherosclerosis

Vascular inflammation plays an important role in atherosclerosis [51], [52]. IL-17 regulates atherosclerosis by activating various signaling pathways that culminate in the activation of transcription factors, including NF-κB, mitogen-activated protein kinases (p38 and ERK1/2), and activator protein 1 (AP-1) [10], [53]. IL-17 signaling stimulates epithelial cells and myeloid cells to produce cytokines and chemokines, which attract innate immune effector cells such as neutrophils and monocytes

Current therapy and IL-17

Statin, a potent lipid-lowering drug, has been widely used for primary and secondary prevention of coronary atherosclerosis. Statin decreases LDL (especially oxLDL), downregulates inflammatory responses, and stabilizes atherosclerotic plaques [73], [74]. Hot el al investigated whether statin modulates the vascular effects of IL-17 by treating HUVECs with IL-17 alone or along with TNF-α, in the presence of absence of mevalonate (an inhibitor of simvastatin) [75]. IL-17 induced IL-6, IL-8,

Conclusions

Recent studies show that IL-17 has spatiotemporal effects on atherosclerosis. Furthermore, discrepancies in data obtained from animal studies partially contribute to the controversial results. Most current studies emphasize on the role of Th17 and IL-17A in atherosclerosis. The role of other members of IL-17 family and IL-17-producing cells should be investigated and taken into consideration for therapeutic application. Further functional and in vivo studies are needed for performing

Acknowledgments

This work is supported by grants from the National Science Foundation of China (No. 81270428, No. 81300999, and No. 81470501).

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ReviewThe paradoxical role of IL-17 in atherosclerosis

Highlights

Abstract

Introduction

Section snippets

IL-17 family

The cellular sources of IL-17

The paradoxical role of IL-17 in atherosclerosis

Current therapy and IL-17

Conclusions

Acknowledgments

Atherosclerosis

J. Biol. Chem.

Immunity

Am. J. Pathol.

Curr. Opin. Immunol.

Cell

Immunity

J. Autoimmun.

Cell

J. Invest. Dermatol.

Immunity

Immunity

J. Am. Coll. Cardiol.

Immunity

J. Biol. Chem.

Clin. Immunol.

Atherosclerosis

Clinical immunology

Atherosclerosis

Int. J. Cardiol.

Lancet

Atherosclerosis

Mechanisms of disease – atherosclerosis – an inflammatory disease

N. Engl. J. Med.

Apolipoprotein mediated, p.o.l.a. presentation, apolipoprotein mediated pathways of lipid antigen presentation

Nature

The immune system in atherosclerosis

Nat. Immunol.

Proinflammatory high-density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid arthritis

Arthritis Rheum.

Accelerated atherosclerosis – an extraarticular feature of rheumatoid arthritis?

Arthritis Rheum.

Patients with severe psoriasis are at increased risk of cardiovascular mortality: cohort study using the General Practice Research Database

Eur. Heart J.

Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque

Arteriosclerosis (Dallas, Tex.)

Immunology of atherosclerosis. Demonstration of heat shock protein 60 expression and T lymphocytes bearing alpha/beta or gamma/delta receptor in human atherosclerotic lesions

Am. J. Pathol.

Structure and signalling in the IL-17 receptor family

Nat. Rev. Immunol.

Differential expression of interleukin-17 family cytokines in intact and complicated human atherosclerotic plaques

J. Pathol.

Expression of IL-17A in human atherosclerotic lesions is associated with increased inflammation and plaque vulnerability

Basic Res. Cardiol.

Cutting edge: interleukin 17 signals through a heteromeric receptor complex

Journal of immunology

Immune and inflammatory mechanisms of atherosclerosis

Annu. Rev. Immunol.

Evidence for a local immune response in atherosclerosis. CD4+ T cells infiltrate lesions of apolipoprotein-E-deficient mice

Am. J. Pathol.

IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis

J. Clin. Invest.

Disease-associated functions of IL-33: the new kid in the IL-1 family

Nat. Rev. Immunol.

Innate lymphoid cells – a proposal for uniform nomenclature

Nat. Rev. Immunol.

Review
The paradoxical role of IL-17 in atherosclerosis