The Detrimental Effects of IFN-α on Vasculogenesis in Lupus Are Mediated by Repression of IL-1 Pathways: Potential Role in Atherogenesis and Renal Vascular Rarefaction

Abstract

Systemic lupus erythematosus (SLE) is characterized by increased vascular risk due to premature atherosclerosis independent of traditional risk factors. We previously proposed that IFN-α plays a crucial role in premature vascular damage in SLE. IFN-α alters the balance between endothelial cell apoptosis and vascular repair mediated by endothelial progenitor cells (EPCs) and myeloid circulating angiogenic cells (CACs). In this study, we demonstrate that IFN-α promotes an antiangiogenic signature in SLE and control EPCs/CACs, characterized by transcriptional repression of IL-1α and β, IL-1R1, and vascular endothelial growth factor A, and upregulation of IL-1R antagonist and the decoy receptor IL-1R2. IL-1β promotes significant improvement in the functional capacity of lupus EPCs/CACs, therefore abrogating the deleterious effects of IFN-α. The beneficial effects from IL-1 are mediated, at least in part, by increases in EPC/CAC proliferation, by decreases in EPC/CAC apoptosis, and by preventing the skewing of CACs toward nonangiogenic pathways. IFN-α induces STAT2 and 6 phosphorylation in EPCs/CACs, and JAK inhibition abrogates the transcriptional antiangiogenic changes induced by IFN-α in these cells. Immunohistochemistry of renal biopsies from patients with lupus nephritis, but not anti-neutrophil cytoplasmic Ab-positive vasculitis, showed this pathway to be operational in vivo, with increased IL-1R antagonist, downregulation of vascular endothelial growth factor A, and glomerular and blood vessel decreased capillary density, compared with controls. Our study introduces a novel putative pathway by which type I IFNs may interfere with vascular repair in SLE through repression of IL-1–dependent pathways. This could promote atherosclerosis and loss of renal function in this disease.

Endothelial progenitor cells: Are they displaying a function in autoimmune disorders?

“…Type I IFNs induce significant impairment of the capacity of EPCs to differentiate into mature endothelial cells and repair the vasculature (Denny et al, 2007;Thacker et al, 2012). In murine models of lupus and atherosclerosis, type I IFN blocking agents abrogates endothelial dysfunction, the prothrombotic phenotype, plaque formation, and abnormal vasculogenesis (Thacker et al, 2010;Mohan et al, 2015;Kahlenberg, 2011). In addition type I IFNs repress expression of the pro-angiogenic cytokine IL-1␤ (41).…”

Integrative Biology Identifies Shared Transcriptional Networks in CKD

“…Underexpressed genes were filtered by applying a cutoff of the median of the non-human Affymetrix control probe sets plus two times their SD. 43 Gene expression datasets are available as CEL files in the Gene Expression Omnibus (submission no. GSE47183).…”

“…This concept is on the basis of the observation that mRNA coexpression patterns can result from common upstream transcriptional regulatory events that determine the transcriptional response in the functional context of a disease. 43,44 Pearson r correlation of tubulointerstitial compartment expression of each candidate gene was computed with the CKD gene expression dataset. Correlations with |r|$0.5 and FDR#0.01 were considered significant.…”

Subclinical Atherosclerosis in Systemic Autoimmune Disorders

“…In particular, lupus EPCs/CACs (myeloid circulating angiogenic cells) have decreased capacity to differentiate into mature ECs and synthesize decreased amounts of the molecules vascular endothelial growth factor and hepatic growth factor (Rajagopalan, Somers et al 2004;Denny, Thacker et al 2007;Lee, Li et al 2007;Moonen, de Leeuw et al 2007;Westerweel, Luijten et al 2007). IFN -a central mediator in lupus pathogenesis-has been recently suggested as a major player of impaired vasculogenesis and atherogenic risk in lupus patients through transcriptional repression of proangiogenic IL-1 pathways, enhancement of foam cell formation, and platelet activation (Lood, Amisten et al 2010;Thacker, Berthier et al 2010;Li, Fu et al 2011). Autoantibodies including antiOxLDL, AECAs (anti-endothelial cell antibodies) and antibodies against heat shock proteins and phospholipids (APLs) have been linked to lupus related CV disease.…”