title: RIPK1 and RIPK3 Kinases Promote Cell-Death-Independent Inflammation by Toll-like Receptor 4.
abstract: Macrophages are a crucial component of the innate immune system in sensing pathogens and promoting local and systemic inflammation. RIPK1 and RIPK3 are homologous kinases, previously linked to activation of necroptotic death. In this study, we have described roles for these kinases as master regulators of pro-inflammatory gene expression induced by lipopolysaccharide, independent of their well-documented cell death functions. In primary macrophages, this regulation was elicited in the absence of caspase-8 activity, required the adaptor molecule TRIF, and proceeded in a cell autonomous manner. RIPK1 and RIPK3 kinases promoted sustained activation of Erk, cFos, and NF-κB, which were required for inflammatory changes. Utilizing genetic and pharmacologic tools, we showed that RIPK1 and RIPK3 account for acute inflammatory responses induced by lipopolysaccharide in vivo; notably, this regulation did not require exogenous manipulation of caspases. These findings identified a new pharmacologically accessible pathway that may be relevant to inflammatory pathologies.
authors.affiliation: Program in Pharmacology and Experimental Therapeutics, Sackler Graduate School, Tufts University, Boston, MA 02111, USA.
authors.forename: Malek
authors.initials: M
authors.lastname: Najjar
authors.affiliation: Medical Scientist Training Program and Program in Neuroscience, Sackler Graduate School, Tufts University, Boston, MA 02111, USA.
authors.forename: Danish
authors.initials: D
authors.lastname: Saleh
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Matija
authors.initials: M
authors.lastname: Zelic
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Shoko
authors.initials: S
authors.lastname: Nogusa
authors.affiliation: Department of Developmental, Molecular & Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Saumil
authors.initials: S
authors.lastname: Shah
authors.affiliation: Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Tai
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Joshua N
authors.initials: JN
authors.lastname: Finger
authors.affiliation: Institute for Genetics, Center for Molecular Medicine and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50674 Cologne, Germany.
authors.forename: Apostolos
authors.initials: A
authors.lastname: Polykratis
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Gough
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: John
authors.initials: J
authors.lastname: Bertin
authors.affiliation: Neuroscience Center and Department of Pediatrics, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Whalen
authors.affiliation: Institute for Genetics, Center for Molecular Medicine and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50674 Cologne, Germany.
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Balachandran
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Kelliher
authors.affiliation: Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Poltorak
authors.affiliation: Program in Pharmacology and Experimental Therapeutics, Sackler Graduate School, Tufts University, Boston, MA 02111, USA.|Department of Developmental, Molecular & Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Alexei
authors.initials: A
authors.lastname: Degterev
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D053181:Caspase 8; D008070:Lipopolysaccharides; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C476286:Ticam1 protein, mouse; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse