Dendritic Cell RIPK1 Maintains Immune Homeostasis by Preventing Inflammation and Autoimmunity.

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.

• Authors: Joanne A O'Donnell, Jesse Lehman, Justine E Roderick, Dalia Martinez-Marin, Matija Zelic, Ciara Doran, Nicole Hermance, Stephen Lyle, Manolis Pasparakis, Katherine A Fitzgerald, Ann Marshak-Rothstein, Michelle A Kelliher
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 200 Issue 2 Pg. 737-748 (01 15 2018) ISSN: 1550-6606 [Electronic] United States
• PMID: 29212904 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2018 by The American Association of Immunologists, Inc.

Chemical References

• Autoantibodies
• Cytokines
• Myeloid Differentiation Factor 88
• Toll-Like Receptors
• RIPK1 protein, human
• Receptor-Interacting Protein Serine-Threonine Kinases

Topics

• Animals
• Autoantibodies (immunology)
• Autoimmunity (genetics)
• B-Lymphocytes (immunology, metabolism)
• Cytokines (metabolism)
• Dendritic Cells (immunology, metabolism)
• Disease Models, Animal
• Fibrosis
• Gene Expression Profiling
• Immunity
• Inflammation (etiology, metabolism, pathology, prevention & control)
• Lymphadenopathy (genetics, immunology, metabolism, pathology)
• Mice
• Mice, Knockout
• Myeloid Differentiation Factor 88 (genetics, metabolism)
• Necrosis (genetics, metabolism)
• Receptor-Interacting Protein Serine-Threonine Kinases (deficiency, genetics, metabolism)
• Signal Transduction
• Toll-Like Receptors (metabolism)