Universität zu Köln

Schreiber, Adrian, Rousselle, Anthony, Becker, Jan Ulrich ORCID: 0000-0003-2929-8085, von Maessenhausen, Anne, Linkermann, Andreas ORCID: 0000-0001-6287-9725 and Kettritz, Ralph (2017). Necroptosis controls NET generation and mediates complement activation, endothelial damage, and autoimmune vasculitis. Proc. Natl. Acad. Sci. U. S. A., 114 (45). S. E9618 - 8. WASHINGTON: NATL ACAD SCIENCES. ISSN 0027-8424

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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 neutrophilmediated 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schreiber, Adrian UNSPECIFIED UNSPECIFIED UNSPECIFIED Rousselle, Anthony UNSPECIFIED UNSPECIFIED UNSPECIFIED Becker, Jan Ulrich UNSPECIFIED orcid.org/0000-0003-2929-8085 UNSPECIFIED von Maessenhausen, Anne UNSPECIFIED UNSPECIFIED UNSPECIFIED Linkermann, Andreas UNSPECIFIED orcid.org/0000-0001-6287-9725 UNSPECIFIED Kettritz, Ralph UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-211449
DOI:	10.1073/pnas.1708247114
Journal or Publication Title:	Proc. Natl. Acad. Sci. U. S. A.
Volume:	114
Number:	45
Page Range:	S. E9618 - 8
Date:	2017
Publisher:	NATL ACAD SCIENCES
Place of Publication:	WASHINGTON
ISSN:	0027-8424
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NEUTROPHIL EXTRACELLULAR TRAPS; ANTINEUTROPHIL CYTOPLASMIC AUTOANTIBODIES; SMALL-VESSEL VASCULITIS; CELL-DEATH; MYELOPEROXIDASE; GLOMERULONEPHRITIS; ANTIBODIES; NECROSIS; KINASE; RIPK3 Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21144