Background/Purpose To study whether the accelerated atherosclerosis in SLE is mediated by type I interferon (IFN-I) through the regulation of endothelial progenitor cells (EPCs) in gld. ApoE-/- C57BL/6 mice under normal chow diet.

Methods The gld. ApoE-/- mice were generated through intercrossing and backcrossing of gld. and ApoE-/- mice on C57BL/6 background. At 20 weeks of age, female gld. ApoE-/- mice were injected with either saline vehicle, synthetic CPG-oligodeoxynucleiotides (CPG-ODN) IRS423 (TLR7/9 agonists) or IRS661 (TLR7 antagonists) twice a week. 4 weeks later, mice were euthanized. Quantitative PCR was applied to detect the mRNA expressions of IFN-I 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. To find out whether EPC function could be modulated by other cytokines, 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 gld. ApoE-/- C57BL/6 mice displayed both aggravated lupus-like disease and atherosclerosis under normal diet. Decreased percentage of peripheral blood and bone marrow EPCs, impaired EPC functions and increased atherosclerotic lesion area were observed in gld. ApoE-/- mice. IRS661 treatment inhibited the expressions of IFN-I inducible genes (including IRF7, MX1, OAS1, OAS2 and IFIT-2), while IRS423 promoted the expressions of these genes. 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 were restored after IRS661 treatment, and deteriorated after IRS423 treatment. 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 impact on EPC regulation.

Conclusion IFN-I, activated through the upregulation of the TLR7/9 signaling, could induce the depletion and dysfunction of both peripheral and BM EPCs in gld. ApoE-/- C57BL/6 mice, thus may contribute to the development of atherosclerosis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/type-i-interferon-induces-the-depletion-and-dysfunction-of-endothelial-progenitor-cells-in-gld-apoe-c57bl6-mice/