Neutrophil subsets and their gene signature associate with vascular inflammation and coronary atherosclerosis in lupus
Neutrophil subsets and their gene signature associate with vascular inflammation and coronary atherosclerosis in lupus
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DOI：
10.1172/jci.insight.99276
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发表时间：
2018-04-19
期刊：
影响因子：
8
通讯作者：
Kaplan, Mariana J.
中科院分区：
文献类型：
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作者：
Carlucci, Philip M.;Purmalek, Monica M.;Kaplan, Mariana J.
背景。系统性红斑狼疮（SLE）与动脉粥样硬化性心血管疾病的风险增加有关，弗雷明汉风险评分（FRS）无法解释这一点。与狼疮促炎性中性粒细胞（低密度粒细胞；LDG）的独特亚群相关的免疫失调可能在增加心血管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、炎症和冠状动脉斑块相关。方法。 SLE 受试者和健康对照者通过量化血管炎症（F-18-氟脱氧葡萄糖-PET/CT [F-18-FDG-PET/CT]）、动脉功能障碍（EndoPAT 和心踝血管指数）和冠状动脉斑块负荷（冠状动脉 CT 血管造影），对血管疾病进行多模式表型分析。通过流式细胞术对 LDG 进行定量。在暴露于高密度脂蛋白（HDL）的放射性标记细胞系中测量胆固醇流出能力。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。即使在调整传统危险因素后，与对照组相比，SLE 患者的血管炎症、动脉僵硬度和非钙化斑块负荷 (NCB) 均有所增加。在 SLE 中，NCB 与 LDG 直接相关，并且在完全调整的模型中与胆固醇流出能力呈负相关。中性粒细胞基因特征反映了狼疮 LDG 中与血管炎症和 NCB 相关的上调最多的基因。结论。患有 SLE 的个体表现出血管炎症、动脉功能障碍和 NCB，这可能解释了报道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的假设：不同的中性粒细胞亚群导致 SLE 中的血管损伤和不稳定的冠状动脉斑块。结果还支持之前的观察结果，即中性粒细胞可能破坏高密度脂蛋白功能，从而促进动脉粥样硬化形成。
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 (F-18-fluorodeoxyglucose-PET/CT [F-18-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.