Section of Immunology and Chronic disease, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Division of Gastroenterology and Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Lupus. 2020 Jul;29(8):825-835. doi: 10.1177/0961203320926253. Epub 2020 Jun 1.
Low-density lipoprotein (LDL) levels are increased by proprotein convertase subtilisin kexin 9 (PCSK9) which targets the LDL receptor. We recently reported that PCSK9 ameliorates dendritic cell (DC) activation by oxidized LDL (OxLDL), which is abundant in atherosclerotic plaques and is also associated with cardiovascular disease (CVD) in systemic lupus erythematosus (SLE). Here, we investigated the role of PCSK9 in SLE.
PCSK9 levels were determined by ELISA among SLE patients ( = 109) and age- and sex-matched population-based controls ( = 91). Common carotid intima-media thickness (IMT) and plaque occurrence were determined by B-mode ultrasound. Plaques were graded by echogenicity. Human peripheral blood monocytes from SLE patients or controls were differentiated into DCs. The effects of PCSK9 and its inhibition by silencing were studied.
PCSK9 levels were non-significantly higher among SLE-patients compared to controls but significantly associated with SLE disease activity, as determined by the Systemic Lupus Activity Measure ( = 0.020) or the SLE Disease Activity Index ( = 0.0178). There was no association between PCSK9 levels and atherosclerosis as determined by IMT, prevalence of plaques or echolucent (potentially vulnerable) plaques. PCSK9 levels were significantly associated with CVD among SLE patients but not after adjusting for age. OxLDL induced PCSK9 in DCs and DC maturation with increased expression of CD86 and HLA-DR. The effects were significantly stronger in DCs from SLE patients than from controls. Silencing of PCSK9 abolished OxLDL-induced DC maturation.
PCSK9 is associated with disease activity in SLE. One underlying cause could be OxLDL promoting DC activation which depends on PCSK9. OxLDL induces PCSK9 - an effect which is higher among SLE patients. PCSK9 could play an unexpected immunological role in SLE.
载脂蛋白转化酶枯草溶菌素 9（PCSK9）可靶向 LDL 受体，从而增加 LDL 水平。我们最近报道，PCSK9 可改善氧化型 LDL（OxLDL）诱导的树突状细胞（DC）活化，OxLDL 在动脉粥样硬化斑块中含量丰富，与系统性红斑狼疮（SLE）中的心血管疾病（CVD）也有关。在此，我们研究了 PCSK9 在 SLE 中的作用。
通过酶联免疫吸附试验（ELISA）测定 109 例 SLE 患者和 91 例年龄和性别匹配的人群对照中的 PCSK9 水平。通过 B 型超声测定颈总动脉内膜中层厚度（IMT）和斑块发生情况。通过回声强度对斑块进行分级。将 SLE 患者或对照者的外周血单核细胞分化为 DC。研究 PCSK9 及其通过沉默的抑制作用的影响。
与对照组相比，SLE 患者的 PCSK9 水平虽无统计学差异，但与 SLE 疾病活动度显著相关，由系统性红斑狼疮活动度评分（SLEDAI）（ = 0.020）或 SLE 疾病活动指数（SLEDAI）（ = 0.0178）确定。PCSK9 水平与 IMT、斑块发生率或低回声（潜在脆弱）斑块（atherosclerosis）无关。PCSK9 水平与 SLE 患者的 CVD 显著相关，但在校正年龄后则无相关性。OxLDL 在 DC 中诱导 PCSK9 并诱导 DC 成熟，增加 CD86 和 HLA-DR 的表达。该作用在 SLE 患者的 DC 中明显强于对照组。沉默 PCSK9 可消除 OxLDL 诱导的 DC 成熟。
PCSK9 与 SLE 中的疾病活动度相关。其潜在原因之一可能是 OxLDL 促进依赖于 PCSK9 的 DC 活化。OxLDL 诱导 PCSK9，在 SLE 患者中这一作用更高。PCSK9 可能在 SLE 中发挥意想不到的免疫作用。
