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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Animals
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Apoptosis / immunology*
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Bone Marrow Cells / immunology
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Caspase 1 / metabolism
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Colitis / genetics
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Colitis / immunology
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Dendritic Cells / immunology*
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Dendritic Cells / transplantation
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Dextran Sulfate
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Enzyme Activation / genetics
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Enzyme Activation / immunology
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Female
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Gene Expression Regulation / immunology
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Inflammation / immunology
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Interleukin-1beta / biosynthesis
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Interleukin-1beta / immunology
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Interleukin-22
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Interleukin-23 / biosynthesis
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Interleukin-23 / immunology
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Interleukins / biosynthesis
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Interleukins / immunology
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Lipopolysaccharides
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Macrophages / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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NF-kappa B p50 Subunit / genetics
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NF-kappa B p50 Subunit / immunology
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Necrosis / immunology*
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RNA, Messenger / biosynthesis
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Receptor-Interacting Protein Serine-Threonine Kinases / genetics*
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Receptors, Interleukin / biosynthesis
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Signal Transduction / immunology
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Transcription Factor RelB / genetics
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Transcription Factor RelB / immunology
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Wound Healing / genetics*
Substances
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IL1B protein, mouse
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Interleukin-1beta
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Interleukin-23
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Interleukins
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Lipopolysaccharides
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NF-kappa B p50 Subunit
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RNA, Messenger
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Receptors, Interleukin
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Relb protein, mouse
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interleukin-22 receptor
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Transcription Factor RelB
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Dextran Sulfate
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Receptor-Interacting Protein Serine-Threonine Kinases
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Ripk3 protein, mouse
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Caspase 1