Dendritic Cell RIPK1 Maintains Immune Homeostasis by Preventing Inflammation and Autoimmunity
| Autor: | Joanne A. O’Donnell, Michelle A. Kelliher, Jesse Lehman, Justine E. Roderick, Katherine A. Fitzgerald, Nicole Hermance, Ann Marshak-Rothstein, Matija Zelic, Stephen Lyle, Manolis Pasparakis, Dalia Martinez-Marin, Ciara G. Doran |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Programmed cell death Necroptosis Immunology Lymphadenopathy Autoimmunity Inflammation Biology Systemic inflammation medicine.disease_cause Mice Necrosis 03 medical and health sciences RIPK1 medicine Animals Immunology and Allergy Autoantibodies Mice Knockout B-Lymphocytes Gene Expression Profiling Toll-Like Receptors Immunity Dendritic Cells Dendritic cell Fibrosis Cell biology Disease Models Animal 030104 developmental biology Receptor-Interacting Protein Serine-Threonine Kinases Myeloid Differentiation Factor 88 Cytokines Signal transduction medicine.symptom Signal Transduction |
| Zdroj: | The Journal of Immunology. 200:737-748 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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