title: Type-I interferon signaling through ISGF3 complex is required for sustained Rip3 activation and necroptosis in macrophages.
abstract: Myeloid cells play a critical role in perpetuating inflammation during various chronic diseases. Recently the death of macrophages through programmed necrosis (necroptosis) has emerged as an important mechanism in inflammation and pathology. We evaluated the mechanisms that lead to the induction of necrotic cell death in macrophages. Our results indicate that type I IFN (IFN-I) signaling is a predominant mechanism of necroptosis, because macrophages deficient in IFN-α receptor type I (IFNAR1) are highly resistant to necroptosis after stimulation with LPS, polyinosinic-polycytidylic acid, TNF-α, or IFN-β in the presence of caspase inhibitors. IFN-I-induced necroptosis occurred through both mechanisms dependent on and independent of Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) and led to persistent phosphorylation of receptor-interacting protein 3 (Rip3) kinase, which resulted in potent necroptosis. Although various IFN-regulatory factors (IRFs) facilitated the induction of necroptosis in response to IFN-β, IRF-9-STAT1- or -STAT2-deficient macrophages were highly resistant to necroptosis. Our results indicate that IFN-β-induced necroptosis of macrophages proceeds through tonic IFN-stimulated gene factor 3 (ISGF3) signaling, which leads to persistent expression of STAT1, STAT2, and IRF9. Induction of IFNAR1/Rip3-dependent necroptosis also resulted in potent inflammatory pathology in vivo. These results reveal how IFN-I mediates acute inflammation through macrophage necroptosis.
authors: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada K1N 6N5;Department of Oncology, University Children's Hospital, University of Zurich, 8032 Zürich, Switzerland;
authors: Scott
authors: S
authors: McComb
authors: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada K1N 6N5;
authors: Erin
authors: E
authors: Cessford
authors: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada K1N 6N5;
authors: Norah A
authors: NA
authors: Alturki
authors: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada K1N 6N5;
authors: Julie
authors: J
authors: Joseph
authors: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada K1N 6N5;
authors: Bojan
authors: B
authors: Shutinoski
authors: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada K1N 6N5;Department of Cellular and Molecular Medicine, Katholieke Universiteit Leuven, 3000 Leuven, Belgium;
authors: Justyna B
authors: JB
authors: Startek
authors: Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140; and.
authors: Ana M
authors: AM
authors: Gamero
authors: Department of Pathology and Molecular Medicine, McMaster University, ON Canada L8S 4L8.
authors: Karen L
authors: KL
authors: Mossman
authors: Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada K1N 6N5; subash.sad@uottawa.ca.
authors: Subash
authors: S
authors: Sad
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D007249:Inflammation; D007370:Interferon Type I / Q000378:metabolism*; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009336:Necrosis; D009842:Oligopeptides / Q000494:pharmacology; D011070:Poly I-C / Q000494:pharmacology; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D007370:Interferon Type I; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D008070:Lipopolysaccharides; D009842:Oligopeptides; D011070:Poly I-C; D053633:Receptor, Interferon alpha-beta; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; C508032:Ifnar1 protein, mouse; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; C485615:Ripk3 protein, mouse; C494228:Isgf3g protein, mouse