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Neutrophil subsets and their gene signature associate with vascular inflammation and coronary atherosclerosis in lupus
Philip M. Carlucci, … , Nehal N. Mehta, Mariana J. Kaplan
Philip M. Carlucci, … , Nehal N. Mehta, Mariana J. Kaplan
Published April 19, 2018
Citation Information: JCI Insight. 2018;3(8):e99276. https://doi.org/10.1172/jci.insight.99276.
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Clinical Medicine Cardiology

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

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Abstract

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 NCT00001372 FUNDING. Intramural Research Program NIAMS/NIH (ZIA AR041199) and Lupus Research Institute

Authors

Philip M. Carlucci, Monica M. Purmalek, Amit K. Dey, Yenealem Temesgen-Oyelakin, Simantini Sakhardande, Aditya A. Joshi, Joseph B. Lerman, Alice Fike, Michael Davis, Jonathan H. Chung, Martin P. Playford, Mohammad Naqi, Pragnesh Mistry, Gustavo Gutierrez-Cruz, Stefania Dell’Orso, Faiza Naz, Taufiq Salahuddin, Balaji Natarajan, Zerai Manna, Wanxia L. Tsai, Sarthak Gupta, Peter Grayson, Heather Teague, Marcus Y. Chen, Hong-Wei Sun, Sarfaraz Hasni, Nehal N. Mehta, Mariana J. Kaplan

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Figure 1

SLE subjects have increased vascular inflammation and coronary plaque compared with controls.

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SLE subjects have increased vascular inflammation and coronary plaque co...
(A and B) Representative 18F-FDG-PET/CT imaging of the aorta in a healthy control (A) compared with SLE (B). (C and D) Representative 18F-FDG-PET/CT scan transverse section at the level of aortic arch from a fused PET/CT scan illustrating increased 18-FDG uptake in the aortic arch of an SLE patient (D) when compared with a matched control (C). Blue and green represents mild uptake, yellow represents moderate uptake, and red represents high FDG uptake. TBR values: control (1.62), SLE (1.81). Magnification is 10 cm for all PET images. (E and F) Multiplanar reconstruction using 320 detector row CCTA scanner of the LAD coronary artery sliced from: (E) 4 different planes of a healthy control (a semiautomated software delineates lumen [inner yellow] from the coronary artery wall [outer orange] showing no noncalcified plaque component to minimal noncalcified plaque component [blue arrow]); and (F) 4 different planes of a sex- and age-matched SLE patient showing moderate to severe NCB component between the 2 contours (blue arrow). Magnification is 4 cm for all CCTA images.

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