The necroptosis adaptor RIPK3 promotes injury-induced cytokine expression and tissue repair

Immunity. 2014 Oct 16;41(4):567-78. doi: 10.1016/j.immuni.2014.09.016.

Abstract

Programmed necrosis or necroptosis is an inflammatory form of cell death that critically requires the receptor-interacting protein kinase 3 (RIPK3). Here we showed that RIPK3 controls a separate, necrosis-independent pathway of inflammation by regulating cytokine expression in dendritic cells (DCs). Ripk3(-/-) bone-marrow-derived dendritic cells (BMDCs) were highly defective in lipopolysaccharide (LPS)-induced expression of inflammatory cytokines. These effects were caused by impaired NF-κB subunit RelB and p50 activation and by impaired caspase 1-mediated processing of interleukin-1β (IL-1β). This DC-specific function of RIPK3 was critical for injury-induced inflammation and tissue repair in response to dextran sodium sulfate (DSS). Ripk3(-/-) mice exhibited an impaired axis of injury-induced IL-1β, IL-23, and IL-22 cytokine cascade, which was partially corrected by adoptive transfer of wild-type DCs, but not Ripk3(-/-) DCs. These results reveal an unexpected function of RIPK3 in NF-κB activation, DC biology, innate inflammatory-cytokine expression, and injury-induced tissue repair.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Apoptosis / immunology*
  • Bone Marrow Cells / immunology
  • Caspase 1 / metabolism
  • Colitis / genetics
  • Colitis / immunology
  • Dendritic Cells / immunology*
  • Dendritic Cells / transplantation
  • Dextran Sulfate
  • Enzyme Activation / genetics
  • Enzyme Activation / immunology
  • Female
  • Gene Expression Regulation / immunology
  • Inflammation / immunology
  • Interleukin-1beta / biosynthesis
  • Interleukin-1beta / immunology
  • Interleukin-23 / biosynthesis
  • Interleukin-23 / immunology
  • Interleukins / biosynthesis
  • Interleukins / immunology
  • Lipopolysaccharides
  • Macrophages / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B p50 Subunit / genetics
  • NF-kappa B p50 Subunit / immunology
  • Necrosis / immunology*
  • RNA, Messenger / biosynthesis
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics*
  • Receptors, Interleukin / biosynthesis
  • Signal Transduction / immunology
  • Transcription Factor RelB / genetics
  • Transcription Factor RelB / immunology
  • Wound Healing / genetics*

Substances

  • IL1B protein, mouse
  • Interleukin-1beta
  • Interleukin-23
  • Interleukins
  • Lipopolysaccharides
  • NF-kappa B p50 Subunit
  • RNA, Messenger
  • Receptors, Interleukin
  • Relb protein, mouse
  • interleukin-22 receptor
  • Transcription Factor RelB
  • Dextran Sulfate
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse
  • Caspase 1
  • interleukin-22