title: 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.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Seth G
authors.initials: SG
authors.lastname: Thacker
authors.forename: Celine C
authors.initials: CC
authors.lastname: Berthier
authors.forename: Deborah
authors.initials: D
authors.lastname: Mattinzoli
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Rastaldi
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.forename: Mariana J
authors.initials: MJ
authors.lastname: Kaplan
mesh_terms: D000328:Adult; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000096:biosynthesis; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008181:Lupus Nephritis / Q000378:metabolism / Q000473:pathology; D008297:Male; D008856:Microscopy, Fluorescence; D018919:Neovascularization, Physiologic; D020411:Oligonucleotide Array Sequence Analysis; D017472:Receptors, Interleukin-1 / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D016898:Interferon-alpha; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D017472:Receptors, Interleukin-1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
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