title: The transcription factor IRF3 triggers "defensive suicide" necrosis in response to viral and bacterial pathogens.
abstract: Although molecular components that execute noninflammatory apoptotic cell death are well defined, molecular pathways that trigger necrotic cell death remain poorly characterized. Here, we show that in response to infection with adenovirus or Listeria monocytogenes, macrophages in vivo undergo rapid proinflammatory necrotic death that is controlled by interferon-regulatory factor 3 (IRF3). The transcriptional activity of IRF3 is, surprisingly, not required for the induction of necrosis, and it proceeds normally in mice deficient in all known regulators of necrotic death or IRF3 activation, including RIPK3, caspases 1, 8, or 11, STING, and IPS1/MAVS. Although L. monocytogenes triggers necrosis to promote the infection, IRF3-dependent necrosis is required for reducing pathogen burden in the models of disseminated infection with adenovirus. Therefore, our studies implicate IRF3 as a principal and nonredundant component of a physiologically regulated necrotic cell-death pathway that operates as an effective innate immune mechanism of host protection against disseminated virus infection.
authors.affiliation: Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Nelson C
authors.initials: NC
authors.lastname: Di Paolo
authors.forename: Konstantin
authors.initials: K
authors.lastname: Doronin
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Baldwin
authors.forename: Thalia
authors.initials: T
authors.lastname: Papayannopoulou
authors.forename: Dmitry M
authors.initials: DM
authors.lastname: Shayakhmetov
mesh_terms: D000258:Adenovirus Infections, Human / Q000276:immunology* / Q000473:pathology; D000260:Adenoviruses, Human / Q000276:immunology*; D000818:Animals; D020169:Caspases / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology; D050838:Interferon Regulatory Factor-3 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D008089:Listeria monocytogenes / Q000276:immunology*; D008088:Listeriosis / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology* / Q000473:pathology* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis / Q000276:immunology / Q000473:pathology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D020169:Caspases