Dendritic Cell RIPK1 Maintains Immune Homeostasis by Preventing Inflammation and Autoimmunity

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

Research output: Contribution to journalArticleResearchpeer-review

18 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)737-748
Number of pages12
JournalJournal of Immunology
Volume200
Issue number2
DOIs
Publication statusPublished - 15 Jan 2018
Externally publishedYes

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