Imbalance between Endothelial Damage and Repair: A Gateway to Cardiovascular Disease in Systemic Lupus Erythematosus
Table 1
A summary of the factors and their mechanisms which contribute to endothelial damage and impaired repair of the endothelium.
Endothelial damage
Description (ref)
Type 1 interferon
Chiefly produced by pDC, IFN is increased in SLE [46, 47] and it stimulates CD4+ cells residing in atherosclerotic plaque to express TRAIL which in turn enhances plaque rupture [48]. IFN induces mDC residing in atherosclerotic plaques to express proinflammatory cytokines and MMPs which destabilize plaques and promote plaque rupture [49]. IFN stimulates platelet aggregation and vascular thrombosis in a P-selectin dependent fashion [50].
Type 2 interferon
Type 2 IFN is produced by a wide range of immunocytes including mDC, activated lymphocytes, and monocytes. It induces monocytes to upregulate IL-1 and TNF which induce the expression of adhesion molecules such as VCAM-1, E-selectin, and ICAM-1 on the endothelium [59].
Proinflammatory cytokines
Major proinflammatory cytokines, including TNF, IL-1, IL-17, and IFNγ which are elevated in SLE, stimulate endothelial expression of adhesion molecules and lead to recruitment of atherogenesis-enhancing monocytes and T cells to the subendothelial space [59, 85]. A clinical study revealed that higher serum TNFα levels were associated with higher coronary calcium score [84], a radiological predictor of coronary artery event.
Immune complexes
Complement-fixed immune complexes upregulate the expression of adhesion molecules on the endothelium [96] However, C1q-containing immune complexes are atheroprotective as they promote clearance of ox-LDL by macrophages [97].
Costimulatory molecules
Endothelium expresses CD137 upon activation by proinflammatory signals such as TNF [72]. Ligation of endothelial CD137 with CD137L expressed on monocytes induces the former to express adhesion molecules and facilitate monocyte migration to the subendothelial space [72–74]. CD40 is expressed on the endothelium, and its interaction with CD40L expressed on T cells induces expression of VCAM-1 which enhances atherosclerosis [77]. A clinical study testing anti-CD40L was however terminated due to the unexpected excessive occurrence of cardiovascular events [79].
Oxidized lipids
Circulating ox-LDL induces endothelial secretion of MCP-1, IL-8, and IL6 which attract DC, T cells, and monocytes. Monocytes are induced to form foam cells under the further influence of ox-LDL and proinflammatory cytokines [58].
Oxidative stress
Oxidative stress increases with higher disease activity of SLE [83]. Reactive oxygen species formed during oxidative stress lead to accumulation of glycation end products which are toxic to the endothelium [63].
Autoantibodies
Annexin-V is a naturally occurring phospholipid-binding anticoagulant protein. Lupus patients demonstrate elevation of the anti-annexin-V antibody, which is related to inferior endothelial function [92–94]. Indeed, antiphospholipid antibodies, in particular the anti-β2-glycoprotein-1 antibodies, interferes the binding between the atheroprotective annexin-V to the phospholipid bilayer of the endothelium [95].
NETs
Antibodies against ribonucleoproteins and LL37 promote NET formation, which induces IFN production by pDC as result of NETs-stimulated lupus neutrophils [99–101], NETs formation leads to activation of vascular thrombosis and endothelial apoptosis [99–101].
Perturbation of vascular repair
Description (ref).
Endothelial progenitor cells
IFN induces EPC apoptosis and the ability of EPC to differentiate to mature endothelium [102, 103]. Vascular repair is impaired by the ability of IFN to repress VEGF and IL-1 and upregulate IL-18 on the endothelium [104]. LDG is another source of IFN apart from pDC which is elevated in patients with SLE. LDG impairs endothelial cell repair, and depletion of LDG restores the ability of EPC to differentiate into mature EPC and repair the endothelial monolayer [106].
