title: Inflammasome activation of IL-18 results in endothelial progenitor cell dysfunction in systemic lupus erythematosus.
abstract: Systemic lupus erythematosus (SLE) is an autoimmune disease with heterogeneous manifestations including severe organ damage and vascular dysfunction leading to premature atherosclerosis. IFN-α has been proposed to have an important role in the development of lupus and lupus-related cardiovascular disease, partly by repression of IL-1 pathways leading to impairments in vascular repair induced by endothelial progenitor cells (EPCs) and circulating angiogenic cells (CACs). Counterintuitively, SLE patients also display transcriptional upregulation of the IL-1β/IL-18 processing machinery, the inflammasome. To understand this dichotomy and its impact on SLE-related cardiovascular disease, we examined cultures of human and murine control or lupus EPC/CACs to determine the role of the inflammasome in endothelial differentiation. We show that caspase-1 inhibition improves dysfunctional SLE EPC/CAC differentiation into mature endothelial cells and blocks IFN-α-mediated repression of this differentiation, implicating inflammasome activation as a crucial downstream pathway leading to aberrant vasculogenesis. Furthermore, serum IL-18 levels are elevated in SLE and correlate with EPC/CAC dysfunction. Exogenous IL-18 inhibits endothelial differentiation in control EPC/CACs and neutralization of IL-18 in SLE EPC/CAC cultures restores their capacity to differentiate into mature endothelial cells, supporting a deleterious effect of IL-18 on vascular repair in vivo. Upregulation of the inflammasome machinery was operational in vivo, as evidenced by gene array analysis of lupus nephritis biopsies. Thus, the effects of IFN-α are complex and contribute to an elevated risk of cardiovascular disease by suppression of IL-1β pathways and by upregulation of the inflammasome machinery and potentiation of IL-18 activation.
authors: Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors: J Michelle
authors: JM
authors: Kahlenberg
authors: Seth G
authors: SG
authors: Thacker
authors: Celine C
authors: CC
authors: Berthier
authors: Clemens D
authors: CD
authors: Cohen
authors: Matthias
authors: M
authors: Kretzler
authors: Mariana J
authors: MJ
authors: Kaplan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D058847:Inflammasomes / Q000276:immunology*; D016898:Interferon-alpha / Q000276:immunology* / Q000378:metabolism; D020382:Interleukin-18 / Q000276:immunology* / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D046228:Microarray Analysis; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D058847:Inflammasomes; D016898:Interferon-alpha; D020382:Interleukin-18