Kim Young Uk, Kee Patrick, Danila Delia, Teng Ba-Bie
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.
Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Immune Netw. 2019 Dec 4;19(6):e41. doi: 10.4110/in.2019.19.e41. eCollection 2019 Dec.
We previously demonstrated that atherogenic (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 gene from LDb mice to generate (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 CD4CD8 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 (CD44CD4) 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, CD44CD4 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.
我们之前证明，缺乏低密度脂蛋白受体（LDLR）和载脂蛋白B mRNA编辑催化多肽-1（Apobec1）的致动脉粥样硬化（LDb）双敲除小鼠血清白细胞介素-17（IL-17）水平升高，T细胞编程向Th17细胞偏移。在本研究中，我们评估了前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK9）在T细胞编程和动脉粥样硬化发生中的作用。我们从LDb小鼠中删除该基因以产生（LTp）三敲除小鼠。对主动脉窦和主动脉中的动脉粥样硬化进行定量分析。通过流式细胞术、酶联免疫吸附测定（ELISA）和实时聚合酶链反应（PCR）分析淋巴细胞。尽管存在血脂异常，但LTp小鼠几乎未出现可检测到的动脉粥样硬化病变。LTp小鼠血浆中的IL-17水平非常低，在主动脉窦中几乎检测不到。在脾脏中，LDb小鼠的CD4CD8细胞和脾细胞数量比LTp小鼠少得多，而LDb小鼠脾脏中产生IL-17的γδTCR T细胞和效应记忆CD4 T细胞（CD44CD4）明显高于LTp小鼠。与LTp小鼠相比，LDb小鼠中Rorc mRNA表达水平升高。用抗CD3抗体再次刺激时，来自LDb小鼠的CD44CD4 T细胞比来自LTp小鼠的分泌更多的IL-17。与LTp小鼠（无PCSK9）相比，来自LDb小鼠（有PCSK9）的T细胞在基础和刺激条件下产生更多的IL-17。尽管存在血脂异常且缺乏LDLR，但LTp小鼠的动脉粥样硬化发生明显减少。这些结果表明，PCSK9与T细胞编程的变化有关，这有助于动脉粥样硬化的发展。
