Skip to main content

Main menu

  • Home
  • Articles
    • Current
    • Special Feature Articles - Most Recent
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • List of Issues
  • Front Matter
    • Front Matter Portal
    • Journal Club
  • News
    • For the Press
    • This Week In PNAS
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Editorial and Journal Policies
    • Submission Procedures
    • Fees and Licenses
  • Submit
  • Submit
  • About
    • Editorial Board
    • PNAS Staff
    • FAQ
    • Accessibility Statement
    • Rights and Permissions
    • Site Map
  • Contact
  • Journal Club
  • Subscribe
    • Subscription Rates
    • Subscriptions FAQ
    • Open Access
    • Recommend PNAS to Your Librarian

User menu

  • Log in
  • My Cart

Search

  • Advanced search
Home
Home
  • Log in
  • My Cart

Advanced Search

  • Home
  • Articles
    • Current
    • Special Feature Articles - Most Recent
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • List of Issues
  • Front Matter
    • Front Matter Portal
    • Journal Club
  • News
    • For the Press
    • This Week In PNAS
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Editorial and Journal Policies
    • Submission Procedures
    • Fees and Licenses
  • Submit
Research Article

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

Adrian Schreiber, Anthony Rousselle, Jan Ulrich Becker, Anne von Mässenhausen, View ORCID ProfileAndreas Linkermann, and View ORCID ProfileRalph Kettritz
  1. aExperimental and Clinical Research Center, Charité–Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany;
  2. bDepartment of Nephrology and Medical Intensive Care, Charité–Universitätsmedizin Berlin, 13353 Berlin, Germany;
  3. cInstitute of Pathology, University Hospital of Cologne, 50937 Cologne, Germany;
  4. dDivision of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universitat Dresden, 01307 Dresden, Germany

See allHide authors and affiliations

PNAS November 7, 2017 114 (45) E9618-E9625; first published October 24, 2017; https://doi.org/10.1073/pnas.1708247114
Adrian Schreiber
aExperimental and Clinical Research Center, Charité–Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany;
bDepartment of Nephrology and Medical Intensive Care, Charité–Universitätsmedizin Berlin, 13353 Berlin, Germany;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: adrian.schreiber@charite.de
Anthony Rousselle
aExperimental and Clinical Research Center, Charité–Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jan Ulrich Becker
cInstitute of Pathology, University Hospital of Cologne, 50937 Cologne, Germany;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anne von Mässenhausen
dDivision of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universitat Dresden, 01307 Dresden, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andreas Linkermann
dDivision of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universitat Dresden, 01307 Dresden, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Andreas Linkermann
Ralph Kettritz
aExperimental and Clinical Research Center, Charité–Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany;
bDepartment of Nephrology and Medical Intensive Care, Charité–Universitätsmedizin Berlin, 13353 Berlin, Germany;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Ralph Kettritz
  1. 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)

  • Article
  • Figures & SI
  • Info & Metrics
  • PDF
Loading

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.

  • ANCA
  • NETs
  • necroptosis
  • complement
  • glomerulonephritis

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.

View Full Text
PreviousNext
Back to top
Article Alerts
Email Article

Thank you for your interest in spreading the word on PNAS.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Necroptosis controls NET generation and mediates complement activation, endothelial damage, and autoimmune vasculitis
(Your Name) has sent you a message from PNAS
(Your Name) thought you would like to see the PNAS web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
NETs and necroptosis in ANCA vasculitis
Adrian Schreiber, Anthony Rousselle, Jan Ulrich Becker, Anne von Mässenhausen, Andreas Linkermann, Ralph Kettritz
Proceedings of the National Academy of Sciences Nov 2017, 114 (45) E9618-E9625; DOI: 10.1073/pnas.1708247114

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
NETs and necroptosis in ANCA vasculitis
Adrian Schreiber, Anthony Rousselle, Jan Ulrich Becker, Anne von Mässenhausen, Andreas Linkermann, Ralph Kettritz
Proceedings of the National Academy of Sciences Nov 2017, 114 (45) E9618-E9625; DOI: 10.1073/pnas.1708247114
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Mendeley logo Mendeley

Article Classifications

  • Biological Sciences
  • Immunology and Inflammation
Proceedings of the National Academy of Sciences: 114 (45)
Table of Contents

Submit

Sign up for Article Alerts

Jump to section

  • Article
    • Abstract
    • Results
    • Discussion
    • Materials and Methods
    • SI Materials and Methods
    • Acknowledgments
    • Footnotes
    • References
  • Figures & SI
  • Info & Metrics
  • PDF

You May Also be Interested in

Smoke emanates from Japan’s Fukushima nuclear power plant a few days after tsunami damage
Core Concept: Muography offers a new way to see inside a multitude of objects
Muons penetrate much further than X-rays, they do essentially zero damage, and they are provided for free by the cosmos.
Image credit: Science Source/Digital Globe.
Water from a faucet fills a glass.
News Feature: How “forever chemicals” might impair the immune system
Researchers are exploring whether these ubiquitous fluorinated molecules might worsen infections or hamper vaccine effectiveness.
Image credit: Shutterstock/Dmitry Naumov.
Venus flytrap captures a fly.
Journal Club: Venus flytrap mechanism could shed light on how plants sense touch
One protein seems to play a key role in touch sensitivity for flytraps and other meat-eating plants.
Image credit: Shutterstock/Kuttelvaserova Stuchelova.
Illustration of groups of people chatting
Exploring the length of human conversations
Adam Mastroianni and Daniel Gilbert explore why conversations almost never end when people want them to.
Listen
Past PodcastsSubscribe
Horse fossil
Mounted horseback riding in ancient China
A study uncovers early evidence of equestrianism in ancient China.
Image credit: Jian Ma.

Similar Articles

Site Logo
Powered by HighWire
  • Submit Manuscript
  • Twitter
  • Facebook
  • RSS Feeds
  • Email Alerts

Articles

  • Current Issue
  • Special Feature Articles – Most Recent
  • List of Issues

PNAS Portals

  • Anthropology
  • Chemistry
  • Classics
  • Front Matter
  • Physics
  • Sustainability Science
  • Teaching Resources

Information

  • Authors
  • Editorial Board
  • Reviewers
  • Subscribers
  • Librarians
  • Press
  • Cozzarelli Prize
  • Site Map
  • PNAS Updates
  • FAQs
  • Accessibility Statement
  • Rights & Permissions
  • About
  • Contact

Feedback    Privacy/Legal

Copyright © 2021 National Academy of Sciences. Online ISSN 1091-6490