Neutrophil subsets and their gene signature associate with vascular inflammation and coronary atherosclerosis in lupus

被引：157

作者：

Carlucci, Philip M. ^{[1
]}

Purmalek, Monica M. ^{[1
]}

Dey, Amit K. ^{[2
]}

Temesgen-Oyelakin, Yenealem ^{[1
]}

Sakhardande, Simantini ^{[1
]}

Joshi, Aditya A. ^{[2
]}

Lerman, Joseph B. ^{[2
]}

Fike, Alice ^{[1
]}

Davis, Michael ^{[1
]}

Chung, Jonathan H. ^{[2
]}

Playford, Martin P. ^{[2
]}

Naqi, Mohammad ^{[1
]}

Mistry, Pragnesh ^{[1
]}

Gutierrez-Cruz, Gustavo ^{[1
]}

Dell'Orso, Stefania ^{[1
]}

Naz, Faiza ^{[1
]}

Salahuddin, Taufiq ^{[2
]}

Natarajan, Balaji ^{[2
]}

Manna, Zerai ^{[1
]}

Tsai, Wanxia L. ^{[1
]}

Gupta, Sarthak ^{[1
]}

Grayson, Peter ^{[1
]}

Teague, Heather ^{[2
]}

Chen, Marcus Y. ^{[2
]}

Sun, Hong-Wei ^{[1
]}

Hasni, Sarfaraz ^{[1
]}

Mehta, Nehal N. ^{[2
]}

Kaplan, Mariana J. ^{[1
]}

机构：

[1] NIAMSD, NIAMS, NIH, Bethesda, MD 20892 USA

[2] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA

来源：

JCI INSIGHT | 2018年 / 3卷 / 08期

关键词：

HIGH-DENSITY-LIPOPROTEIN; PEPTIDYLARGININE DEIMINASE INHIBITION; CHOLESTEROL EFFLUX CAPACITY; TO-LYMPHOCYTE RATIO; COMPUTED-TOMOGRAPHY; CARDIOVASCULAR-RISK; ACCELERATED ATHEROSCLEROSIS; INTRAVASCULAR ULTRASOUND; NONINVASIVE ASSESSMENT; PLAQUE CHARACTERISTICS;

D O I：

10.1172/jci.insight.99276

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页数：15

共 63 条

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