title: Distinct Kinase-Independent Role of RIPK3 in CD11c+Mononuclear Phagocytes in Cytokine-Induced Tissue Repair.
abstract: Receptor interacting protein kinase 3 (RIPK3) induces necroptosis, a type of regulated necrosis, through its kinase domain and receptor interacting protein (RIP) homotypic interaction motif (RHIM). In addition, RIPK3 has been shown to regulate NLRP3 inflammasome and nuclear factor κB (NF-κB) activation. However, the relative contribution of these signaling pathways to RIPK3-dependent inflammation in distinct immune effectors is unknown. To investigate these questions, we generated RIPK3-GFP reporter mice. We found that colonic CD11c+CD11b+CD14+mononuclear phagocytes (MNPs) expressed the highest level of RIPK3 in the lamina propria. Consequently, deletion of the RIPK3 RHIM in CD11c+cells alone was sufficient to impair dextran sodium sulfate (DSS)-induced interleukin (IL)-23 and IL-1β expression, leading to severe intestinal inflammation. In contrast, mice expressing kinase inactive RIPK3 were not hypersensitive to DSS. Thus, a key physiological function of RIPK3 is to promote reparative cytokine expression through intestinal CD11c+MNPs in a kinase- and necroptosis-independent manner.
authors.affiliation: Department of Pathology, Immunology and Microbiology Program, University of Massachusetts Medical School, Worcester, MA 01605, 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 01605, USA.
authors.forename: Sakthi
authors.initials: S
authors.lastname: Balaji
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19422, USA.
authors.forename: John
authors.initials: J
authors.lastname: Bertin
authors.affiliation: Host Defense Discovery Performance Unit, Infectious Disease Therapy Area, GlaxoSmithKline, Collegeville, PA 19422, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Gough
authors.affiliation: Department of Pathology, Immunology and Microbiology Program, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: francis.chan@umassmed.edu.
authors.forename: Francis Ka-Ming
authors.initials: FK
authors.lastname: Chan
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018845:CD11 Antigens / Q000378:metabolism*; D000073883:CX3C Chemokine Receptor 1 / Q000378:metabolism; D003092:Colitis / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D003106:Colon / Q000473:pathology; D016207:Cytokines / Q000494:pharmacology*; D016264:Dextran Sulfate; D017353:Gene Deletion; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D010586:Phagocytes / Q000187:drug effects / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D018845:CD11 Antigens; D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D016207:Cytokines; D049452:Green Fluorescent Proteins; D016264:Dextran Sulfate; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse
keywords: IL-1b; IL-23; RHIM; RIPK3; colitis; dextran sodium sulfate; inflammation; injury; necroptosis; tissue repair