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Necroptosis controls NET generation and mediates complement activation, endothelial damage, and autoimmune vasculitis

Item Type:Article
Title:Necroptosis controls NET generation and mediates complement activation, endothelial damage, and autoimmune vasculitis
Creators Name:Schreiber, A. and Rousselle, A. and Becker, J.U. and von Mässenhausen, A. and Linkermann, A. and Kettritz, R.
Abstract:Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitutes life-threatening autoimmune diseases affecting every organ, including the kidneys, where they cause necrotizing crescentic glomerulonephritis. ANCA activates neutrophils and activated neutrophils damage the endothelium, leading to vascular inflammation and necrosis. Better understanding of neutrophil-mediated AAV disease mechanisms may reveal novel treatment strategies. Here we report that ANCA induces neutrophil extracellular traps (NETs) via receptor-interacting protein kinase (RIPK) 1/3- and mixed-lineage kinase domain-like (MLKL)-dependent necroptosis. NETs from ANCA-stimulated neutrophils caused endothelial cell (EC) damage in vitro. This effect was prevented by (i) pharmacologic inhibition of RIPK1 or (ii) enzymatic NET degradation. The alternative complement pathway (AP) was recently implicated in AAV, and C5a inhibition is currently being tested in clinical studies. We observed that NETs provided a scaffold for AP activation that in turn contributed to EC damage. We further established the in vivo relevance of NETs and the requirement of RIPK1/3/MLKL-dependent necroptosis, specifically in the bone marrow-derived compartment, for disease induction using murine AAV models and in human kidney biopsies. In summary, we identified a mechanistic link between ANCA-induced neutrophil activation, necroptosis, NETs, the AP, and endothelial damage. RIPK1 inhibitors are currently being evaluated in clinical trials and exhibit a novel therapeutic strategy in AAV.
Keywords:ANCA, NETs, Necroptosis, Complement, Glomerulonephritis, Animals, Mice
Source:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424
Publisher:National Academy of Sciences (U.S.A.)
Volume:114
Number:45
Page Range:E9618-E9625
Date:7 November 2017
Official Publication:https://doi.org/10.1073/pnas.1708247114
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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