Type-I interferon signaling through ISGF3 complex is required for sustained Rip3 activation and necroptosis in macrophages

Scott McComb, Erin Cessford, Norah A. Alturki, Julie Joseph, Bojan Shutinoski, Justyna B. Startek, Ana M. Gamero, Karen L. Mossman, Subash Sad

Research output: Contribution to journalArticlepeer-review

156 Scopus citations

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.

Original languageEnglish
Pages (from-to)E3206-E3213
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number31
DOIs
StatePublished - Jul 5 2014

Keywords

  • Animals
  • Apoptosis/drug effects
  • Enzyme Activation/drug effects
  • Inflammation
  • Interferon Type I/metabolism
  • Interferon-Stimulated Gene Factor 3, gamma Subunit/metabolism
  • Lipopolysaccharides/pharmacology
  • Macrophages/drug effects
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Necrosis
  • Oligopeptides/pharmacology
  • Poly I-C/pharmacology
  • Receptor, Interferon alpha-beta/deficiency
  • Receptor-Interacting Protein Serine-Threonine Kinases/deficiency
  • Signal Transduction/drug effects
  • Tumor Necrosis Factor-alpha/pharmacology

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