Background Patients with systemic lupus erythematosus (SLE) had reduced number and dysfunction of endothelial progenitor cells (EPC), which were linked to the high incidence of premature atherosclerosis in various experimental and clinical studies. To study the accelerated atherosclerosis in SLE, we have established the apolipoprotein E-deficient (ApoE(-/-)) and Fas ligand-deficient (gld.) C57BL/6 mice model that displayed both aggravated lupus-like disease and atherosclerosis under normal diet.
Objectives This study is aimed to examine whether the development of atherosclerosis in gld. ApoE-/- C57B/6 mice is mediated by type I interferon (IFN) through the regulation of the EPC.
Methods At 20 weeks of age, female gld. ApoE-/- mice were injected with either saline vehicle, synthetic CPG-oligodeoxynucleiotides (CPG-ODN) IRS423 (TLR7/9 agonists, 0.125 mg/kg) or IRS661 (TLR7 antagonists, 0.125 mg/kg) twice a week. 4 weeks later, mice were euthanized. Quantitative PCR was applied to detect the mRNA expressions of type I IFN inducible genes. EPCs in peripheral blood and bone marrow were recognized as Sca-1+CD309+ cells by FACS. The capacities of EPC to differentiate into mature endothelial cells, to re-adherent and to form vascular-like structure were measured to determine EPC functions. The atherosclerotic lesions in aorta were stained with 0.5% Oil Red O, and their associations with IFN gene expressions, EPC numbers and functions were analyzed. To find out whether EPC function could be modulated by type I IFN specifically, EPCs from 24 weeks old female gld. ApoE-/- mice were cultured in vitro in the presence of either IFN-α, IL-1β, TNF-α, IRS423 (1μM), IRS954 (1μM) or saline vehicle control for 24 hours.
Results Decreased percentage of peripheral blood and bone marrow EPCs, impaired EPC functions and increased atherosclerotic lesion area were observed in gld. ApoE-/- mice. IRS661 could restore the number of EPCs and the ability of EPC to form normal endothelial cells monolayer, to form cavity structure and to re-adherent in gld. ApoE-/- mice, while IRS423 led to an opposite effect. Meanwhile, atherosclerotic lesion area in gld. ApoE-/- mice was also aggravated by IRS423, but improved after IRS661 treatment. IRS661 treatment inhibited the expressions of IRF7, MX1, OAS1, OAS2 and IFIT-2, while IRS423 promoted the expressions of these type I IFN inducible genes. The expressions of IFN-I inducible genes were closely associated with EPC functions and atherosclerotic lesions. In vitro experiments showed that only recombinant IFN-α could affect EPC functions, while other interventions including IL-1β, TNF-α, IRS423 and IRS661 did not have a direct role on EPC regulation.
Conclusions Type I interferon overproduction caused by the activation of the TLR7/9 signaling could induce the depletion and dysfunction of EPCs, thus may contribute to the development of atherosclerosis in gld. ApoE-/- mice.
Disclosure of Interest : None declared
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