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Endothelial NF-κB blockade abrogates ANCA-induced GN

Item Type:Article
Title:Endothelial NF-κB blockade abrogates ANCA-induced GN
Creators Name:Choi, M. and Schreiber, A. and Eulenberg-Gustavus, C. and Scheidereit, C. and Kamps, J. and Kettritz, R.
Abstract:ANCA-associated vasculitis (AAV) is a highly inflammatory condition in which ANCA-activated neutrophils interact with the endothelium, resulting in necrotizing vasculitis. We tested the hypothesis that endothelial NF-κB mediates necrotizing crescentic GN (NCGN) and provides a specific treatment target. Reanalysis of kidneys from previously examined murine NCGN disease models revealed NF-κB activation in affected kidneys, mostly as a p50/p65 heterodimer, and increased renal expression of NF-κB-dependent tumor necrosis factor α (TNF-α). NF-κB activation positively correlated with crescent formation, and nuclear phospho-p65 staining showed NF-κB activation within CD31-expressing endothelial cells (ECs) in affected glomeruli. Therefore, we studied the effect of ANCA on NF-κB activation in neutrophil/EC cocultures in vitro ANCA did not activate NF-κB in primed human neutrophils, but ANCA-stimulated primed neutrophils activated NF-κB in ECs, at least in part via TNF-α release. This effect increased endothelial gene transcription and protein production of NF-κB-regulated interleukin-8. Moreover, upregulation of endothelial NF-κB promoted neutrophil adhesion to EC monolayers, an effect that was inhibited by a specific IKKβ inhibitor. In a murine NCGN model, prophylactic application of E-selectin-targeted immunoliposomes packed with p65 siRNA to downregulate endothelial NF-κB significantly reduced urine abnormalities, renal myeloid cell influx, and NCGN. Increased glomerular endothelial phospho-p65 staining in patients with AAV indicated that NF-κB is activated in human NCGN also. We suggest that ANCA-stimulated neutrophils activate endothelial NF-κB, which contributes to NCGN and provides a potential therapeutic target in AAV.
Keywords:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Cultured Cells, Glomerulonephritis, Kidney Glomerulus, NF-kappa B, Necrosis, Neutrophil Activation, Vascular Endothelium, Animals, Mice
Source:Journal of the American Society of Nephrology
ISSN:1046-6673
Publisher:American Society of Nephrology (U.S.A.)
Volume:28
Number:11
Page Range:3191-3204
Date:November 2017
Official Publication:https://doi.org/10.1681/ASN.2016060690
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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