title: The necroptosis adaptor RIPK3 promotes injury-induced cytokine expression and tissue repair.
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.
authors.affiliation: Department of Pathology, Immunology and Microbiology Program, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Kenta
authors.initials: K
authors.lastname: Moriwaki
authors.affiliation: Department of Pathology, Immunology and Microbiology Program, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Sakthi
authors.initials: S
authors.lastname: Balaji
authors.affiliation: Department of Pathology, Immunology and Microbiology Program, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: McQuade
authors.affiliation: Department of Pathology, Immunology and Microbiology Program, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Malhotra
authors.affiliation: Department of Pathology, Immunology and Microbiology Program, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Joonsoo
authors.initials: J
authors.lastname: Kang
authors.affiliation: Department of Pathology, Immunology and Microbiology Program, University of Massachusetts Medical School, Worcester, MA 01655, USA. Electronic address: francis.chan@umassmed.edu.
authors.forename: Francis Ka-Ming
authors.initials: FK
authors.lastname: Chan
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology; D020170:Caspase 1 / Q000378:metabolism; D003092:Colitis / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D016264:Dextran Sulfate; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000276:immunology; D053759:Interleukin-23 / Q000096:biosynthesis / Q000276:immunology; D007378:Interleukins / Q000096:biosynthesis / Q000276:immunology; D008070:Lipopolysaccharides; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000276:immunology; D009336:Necrosis / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics*; D018123:Receptors, Interleukin / Q000096:biosynthesis; D015398:Signal Transduction / Q000276:immunology; D051841:Transcription Factor RelB / Q000235:genetics / Q000276:immunology; D014945:Wound Healing / Q000235:genetics*; D000097043:Interleukin-22
chemical_list: D020170:Caspase 1; D016264:Dextran Sulfate; D053583:Interleukin-1beta; D053759:Interleukin-23; D007378:Interleukins; D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; D012333:RNA, Messenger; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D018123:Receptors, Interleukin; D051841:Transcription Factor RelB; D000097043:Interleukin-22; C587672:IL1B protein, mouse; C497594:Relb protein, mouse; C415369:interleukin-22 receptor; C485615:Ripk3 protein, mouse