A Critical Role of PCSK9 in Mediating IL-17-Producing T Cell Responses in Hyperlipidemia

Young Uk Kim; Patrick Kee; Delia Danila; Ba-Bie Teng

doi:10.4110/in.2019.19.e41

A Critical Role of PCSK9 in Mediating IL-17-Producing T Cell Responses in Hyperlipidemia

Immune Netw. 2019 Dec 4;19(6):e41. doi: 10.4110/in.2019.19.e41. eCollection 2019 Dec.

Authors

Young Uk Kim¹, Patrick Kee², Delia Danila², Ba-Bie Teng^{3

4}

Affiliations

¹ Center for Immunology and Autoimmune Diseases, The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
² Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
³ Center for Human Genetics, The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
⁴ Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.

Abstract

We previously demonstrated that atherogenic Ldlr ^-/- Apobec1 ^-/- (LDb) double knockout mice lacking both low-density lipoprotein receptor (LDLR) and apolipoprotein B mRNA-editing catalytic polypeptide-1 (Apobec1) had increased serum IL-17 levels, with T cell programming shifted towards Th17 cells. In this study, we assessed the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in T cell programming and atherogenesis. We deleted the Pcsk9 gene from LDb mice to generate Ldlr ^-/- Apobec1 ^-/- Pcsk9 ^-/- (LTp) triple knockout mice. Atherosclerosis in the aortic sinus and aorta were quantitated. Lymphoid cells were analyzed by flow cytometry, ELISA and real-time PCR. Despite of dyslipidemia, LTp mice developed barely detectable atherosclerotic lesions. The IL-17, was very low in plasma and barely detectable in the aortic sinus in the LTp mice. In the spleen, the number of CD4⁺CD8^- cells and splenocytes were much lower in the LDb mice than LTp mice, whereas, the IL-17-producing cells of γδTCR⁺ T cells and effector memory CD4⁺ T cells (CD44^hiCD4⁺) in the spleen were significantly higher in the LDb mice than in the LTp mice. The Rorc mRNA expression levels were elevated in LDb mice compared to LTp mice. When re-stimulated with an anti-CD3 Ab, CD44^hiCD4⁺ T cells from LDb mice secreted more IL-17 than those from LTp mice. T cells from LDb mice (with PCSK9) produce more IL-17 at basal and stimulated conditions when compared with LTp mice (without PCSK9). Despite the dyslipidemic profile and the lack of LDLR, atherogenesis is markedly reduced in LTp mice. These results suggest that PCSK9 is associated with changes in T cell programming that contributes to the development of atherosclerosis.

Keywords: Atherosclerosis; IL-17; PCSK9; T-cells.