Universität zu Köln

O'Donnell, Joanne A., Lehman, Jesse, Roderick, Justine E., Martinez-Marin, Dalia ORCID: 0000-0002-5476-4618, Zelic, Matija, Doran, Ciara, Hermance, Nicole, Lyle, Stephen, Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Fitzgerald, Katherine A., Marshak-Rothstein, Ann and Kelliher, Michelle A. (2018). Dendritic Cell RIPK1 Maintains Immune Homeostasis by Preventing Inflammation and Autoimmunity. J. Immunol., 200 (2). S. 737 - 749. BETHESDA: AMER ASSOC IMMUNOLOGISTS. ISSN 1550-6606

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Abstract

Necroptosis is a form of cell death associated with inflammation; however, the biological consequences of chronic necroptosis are unknown. Necroptosis is mediated by RIPK1, RIPK3, and MLKL kinases but in hematopoietic cells RIPK1 has anti-inflammatory roles and functions to prevent necroptosis. Here we interrogate the consequences of chronic necroptosis on immune homeostasis by deleting Ripk1 in mouse dendritic cells. We demonstrate that deregulated necroptosis results in systemic inflammation, tissue fibrosis, and autoimmunity. We show that inflammation and autoimmunity are prevented upon expression of kinase inactive RIPK1 or deletion of RIPK3 or MLKL. We provide evidence that the inflammation is not driven by microbial ligands, but depends on the release of danger-associated molecular patterns and MyD88-dependent signaling. Importantly, although the inflammation is independent of type I IFN and the nucleic acid sensing TLRs, blocking these pathways rescues the autoimmunity. These mouse genetic studies reveal that chronic necroptosis may underlie human fibrotic and autoimmune disorders.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code O'Donnell, Joanne A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lehman, Jesse UNSPECIFIED UNSPECIFIED UNSPECIFIED Roderick, Justine E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Martinez-Marin, Dalia UNSPECIFIED orcid.org/0000-0002-5476-4618 UNSPECIFIED Zelic, Matija UNSPECIFIED UNSPECIFIED UNSPECIFIED Doran, Ciara UNSPECIFIED UNSPECIFIED UNSPECIFIED Hermance, Nicole UNSPECIFIED UNSPECIFIED UNSPECIFIED Lyle, Stephen UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Fitzgerald, Katherine A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Marshak-Rothstein, Ann UNSPECIFIED UNSPECIFIED UNSPECIFIED Kelliher, Michelle A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-198869
DOI:	10.4049/jimmunol.1701229
Journal or Publication Title:	J. Immunol.
Volume:	200
Number:	2
Page Range:	S. 737 - 749
Date:	2018
Publisher:	AMER ASSOC IMMUNOLOGISTS
Place of Publication:	BETHESDA
ISSN:	1550-6606
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SYSTEMIC-LUPUS-ERYTHEMATOSUS; TOLL-LIKE RECEPTORS; MIXED LINEAGE KINASE; ACTIVATE B-CELLS; IN-VIVO; PSEUDOKINASE MLKL; GERMINAL-CENTERS; DEFICIENT MICE; CUTTING EDGE; TNF RECEPTOR Multiple languages Immunology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/19886