Analyses of ancient dog DNA suggest that dogs were likely domesticated from Eurasian wolves around 23,000 years ago, possibly in Siberia.
Image credit: Pixabay/Chiemsee2016.
Edited by Michael Karin, University of California San Diego School of Medicine, La Jolla, CA, and approved September 28, 2017 (received for review May 18, 2017)
Significance
In this report, we provide evidence of a mechanistic link between antineutrophil cytoplasmic antibody (ANCA)-induced neutrophil activation, regulated necrosis (necroptosis), generation of neutrophil extracellular traps, complement activation, and endothelial cell damage with consecutive vasculitis and glomerulonephritis in autoimmune ANCA-induced vasculitis (AAV). We now show that inhibition of necroptosis-inducing kinases completely prevents ANCA vasculitis and establish a link to activation of the complement system. We suggest that these findings significantly extend our understanding of the pathogenesis of AAV and especially the tight regulation of neutrophil cell death therein. In addition, specific necroptosis inhibitors are currently being evaluated in clinical studies and can possibly complement existing therapeutic strategies in AAV.
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.
Footnotes
- ↵1To whom correspondence should be addressed. Email: adrian.schreiber{at}charite.de.
Author contributions: A.S., A.L., and R.K. designed research; A.S., A.R., J.U.B., and A.v.M. performed research; A.S. and A.L. contributed new reagents/analytic tools; A.S., J.U.B., and A.L. analyzed data; and A.S., A.R., J.U.B., A.L., and R.K. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1708247114/-/DCSupplemental.
Published under the PNAS license.
NETs and necroptosis in ANCA vasculitis
Article Classifications
- Biological Sciences
- Immunology and Inflammation
Sign up for Article Alerts
Jump to section
You May Also be Interested in
Pollen seasons have lengthened by 20 days and pollen concentrations have increased by 21% from 1990 to 2018 in North America, and anthropogenic climate change is a likely factor.
Image credit: William R. L. Anderegg.
Conservation efforts must be better coordinated across national borders, and the impacts of border barriers on species must be mitigated as the climate changes.
Image credit: Stephen G. Willis.
Vaccination efforts must be coupled with aggressive community-based COVID point-of-care testing so that cases of asymptomatic infection are rapidly identified.
Image credit: Shutterstock/zstock.
The innovative solution entails simply drying and using whole bacteria, with no need to separate and purify the reagent products.
Image credit: Shutterstock/motorolka.