中性粒细胞亚群及其基因特征与狼疮患者的血管炎症和冠状动脉粥样硬化相关。
Neutrophil subsets and their gene signature associate with vascular inflammation and coronary atherosclerosis in lupus.
机构信息
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and.
National Heart, Lung and Blood Institute (NHLBI), NIH, Bethesda, Maryland, USA.
出版信息
JCI Insight. 2018 Apr 19;3(8). doi: 10.1172/jci.insight.99276.
BACKGROUND
Systemic lupus erythematosus (SLE) is associated with enhanced risk of atherosclerotic cardiovascular disease not explained by Framingham risk score (FRS). Immune dysregulation associated to a distinct subset of lupus proinflammatory neutrophils (low density granulocytes; LDGs) may play key roles in conferring enhanced CV risk. This study assessed if lupus LDGs are associated with in vivo vascular dysfunction and inflammation and coronary plaque.
METHODS
SLE subjects and healthy controls underwent multimodal phenotyping of vascular disease by quantifying vascular inflammation (18F-fluorodeoxyglucose-PET/CT [18F-FDG-PET/CT]), arterial dysfunction (EndoPAT and cardio-ankle vascular index), and coronary plaque burden (coronary CT angiography). LDGs were quantified by flow cytometry. Cholesterol efflux capacity was measured in high-density lipoprotein-exposed (HDL-exposed) radioactively labeled cell lines. Whole blood RNA sequencing was performed to assess associations between transcriptomic profiles and vascular phenotype.
RESULTS
Vascular inflammation, arterial stiffness, and noncalcified plaque burden (NCB) were increased in SLE compared with controls even after adjustment for traditional risk factors. In SLE, NCB directly associated with LDGs and associated negatively with cholesterol efflux capacity in fully adjusted models. A neutrophil gene signature reflective of the most upregulated genes in lupus LDGs associated with vascular inflammation and NCB.
CONCLUSION
Individuals with SLE demonstrate vascular inflammation, arterial dysfunction, and NCB, which may explain the higher reported risk for acute coronary syndromes. The association of LDGs and neutrophil genes with vascular disease supports the hypothesis that distinct neutrophil subsets contribute to vascular damage and unstable coronary plaque in SLE. Results also support previous observations that neutrophils may disrupt HDL function and thereby promote atherogenesis.
TRIAL REGISTRATION
Clinicaltrials.gov NCT00001372FUNDING. Intramural Research Program NIAMS/NIH (ZIA AR041199) and Lupus Research Institute.
背景
系统性红斑狼疮（SLE）与动脉粥样硬化性心血管疾病风险增加有关，但不能用弗莱明翰风险评分（FRS）来解释。与狼疮促炎中性粒细胞（低密度粒细胞；LDG）的一个特定亚群相关的免疫失调可能在赋予增强的 CV 风险方面发挥关键作用。本研究评估了狼疮 LDG 是否与体内血管功能障碍和炎症以及冠状动脉斑块有关。
方法
SLE 患者和健康对照者接受血管疾病的多模式表型分析，通过量化血管炎症（18F-氟脱氧葡萄糖-PET/CT[18F-FDG-PET/CT]）、动脉功能障碍（EndoPAT 和心踝血管指数）和冠状动脉斑块负担（冠状动脉 CT 血管造影）。通过流式细胞术定量 LDG。在高密度脂蛋白暴露（HDL 暴露）放射性标记细胞系中测量胆固醇外排能力。进行全血 RNA 测序以评估转录组谱与血管表型之间的关联。
结果
与对照组相比，SLE 患者的血管炎症、动脉僵硬和非钙化斑块负担（NCB）增加，即使在调整了传统危险因素后也是如此。在 SLE 中，NCB 与 LDG 直接相关，并在完全调整的模型中与胆固醇外排能力呈负相关。反映狼疮 LDG 中上调最明显基因的中性粒细胞基因特征与血管炎症和 NCB 相关。
结论
SLE 患者表现出血管炎症、动脉功能障碍和 NCB，这可能解释了报告的急性冠状动脉综合征风险较高的原因。LDG 和中性粒细胞基因与血管疾病的关联支持这样一种假设，即不同的中性粒细胞亚群可能导致 SLE 中的血管损伤和不稳定的冠状动脉斑块。结果还支持以前的观察结果，即中性粒细胞可能破坏 HDL 功能，从而促进动脉粥样硬化的发生。
试验注册
Clinicaltrials.gov NCT00001372 基金。NIAMS/NIH 内部研究计划（ZIA AR041199）和狼疮研究协会。
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