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.
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.
Thacker
Seth G
SG
Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Berthier
Celine C
CC
Mattinzoli
Deborah
D
Rastaldi
Maria Pia
MP
Kretzler
Matthias
M
Kaplan
Mariana J
MJ
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
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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