Interleukin-17-Producing CD4+ T Cells Promote Inflammatory Response and Foster Disease Progression in Hyperlipidemic Patients and Atherosclerotic Mice.

Yin Wang,Tao Deng,Zhangyou Yang,Wenming Li,Chao Yu,Tingting Wang,Yao Zou,Limei Ma,Ruihong Yu,Tingrui Zhao,Zhiyi Yuan

doi:10.3389/fcvm.2021.667768

Abstract

Atherosclerosis is a chronic inflammatory disease. Interleukin-17-producing CD4+ T cells (Th17 cells) play important roles in the progression of atherosclerosis. However, most of the studies were focused on the advanced stage of atherosclerosis. In the current study, we investigated the roles of Th17 cells, relevant mechanisms in hyperlipidemic patients, and different stages of atherosclerotic mice. Human blood samples were collected, and percentages of Th17 cells, macrophages, and neutrophils were analyzed by flow cytometry. ApoE−/− mice were fed with high-fat diet (HFD) and sacrificed at different time points to evaluate the infiltration of inflammatory cells at different stages of atherosclerosis. Furthermore, essential mechanisms of IL-17A in atherosclerotic inflammatory milieu formation were studied in vivo by intraperitoneal injection with monoclonal anti-murine IL-17 antibody. Our study reveals the higher percentages of Th17 cells, monocytes, and neutrophils in hyperlipidemic patients compared to healthy donors. Meanwhile, we also identify an infiltration of Th17 cells in the early stage of atherosclerosis (4 weeks after HFD), which maintains at high level until late stage of atherosclerosis (20 weeks after HFD). What is more, inflammatory cells including macrophages and neutrophils were also accumulated in atherosclerotic lesions. Neutralization of IL-17 in ApoE−/− mice resulted in less infiltration of macrophages and neutrophils and smaller atherosclerotic lesions. Importantly, in accordance with what is found in the mouse model, positive correlations between Th17 cells and macrophages or neutrophils were observed in hyperlipidemic patients. In conclusion, our clinical and mouse model data together reveal a pro-atherogenic role of Th17 cells through the promotion of inflammation in hyperlipidemic conditions and different stages of atherosclerosis, which further supports the notion that IL-17 may be a therapy target for the treatment of atherosclerosis.

Highlights

Atherosclerosis is the main cause of cardiovascular disease, which is the leading cause of mortality worldwide [1]
As most of the atherosclerosis cases resulted from hyperlipidemia, these results indicate that Th17 cell may play a pivotal role in early atherosclerosis
Our findings reveal that Th17 cells increased since early atherosclerosis, and the neutralization of IL-17 results in smaller atheroma plaque formation in ApoE−/− mice fed with high-fat diet (HFD)

Summary

Introduction

Atherosclerosis is the main cause of cardiovascular disease, which is the leading cause of mortality worldwide [1]. The pathogenesis of atherosclerosis is very complicated, with a key role for immune cells and inflammation in conjunction with hyperlipidemia, especially elevated (modified) low-density lipoprotein (LDL) levels [2]. Lesions of atherosclerosis contain macrophages, T cells, and other immune cells, together with cholesterol that infiltrates from the blood [3]. As part of the adaptive immune system, T cells actively participate in regulating local and systemic inflammation during atherosclerosis [5]. Tregs are subdivided into two types (natural and induced) depending on their origin [10]. Both natural Tregs and iTregs are important for protection against atherosclerosis, either by direct effects on T cells or through deactivation of dendritic cells [11]

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Results

Conclusion