Type I interferon antagonism of the JMJD3-IRF4 pathway modulates macrophage activation and polarization

Kevin Ming-Chin Lee, Adrian A. Achuthan, David P. De Souza, Tanya J. Lupancu, Katrina J. Binger, Man K.S. Lee, Yangsong Xu, Malcolm J. McConville, Nicole A. de Weerd, Dragana Dragoljevic, Paul J. Hertzog, Andrew J. Murphy, John A. Hamilton, Andrew J. Fleetwood

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20 Citations (Scopus)


Metabolic adaptations can directly influence the scope and scale of macrophage activation and polarization. Here we explore the impact of type I interferon (IFNβ) on macrophage metabolism and its broader impact on cytokine signaling pathways. We find that IFNβ simultaneously increased the expression of immune-responsive gene 1 and itaconate production while inhibiting isocitrate dehydrogenase activity and restricting α-ketoglutarate accumulation. IFNβ also increased the flux of glutamine-derived carbon into the tricarboxylic acid cycle to boost succinate levels. Combined, we identify that IFNβ controls the cellular α-ketoglutarate/succinate ratio. We show that by lowering the α-ketoglutarate/succinate ratio, IFNβ potently blocks the JMJD3-IRF4-dependent pathway in GM-CSF and IL-4 activated macrophages. The suppressive effects of IFNβ on JMJD3-IRF4-dependent responses, including M2 polarization and GM-CSF-induced inflammatory pain, were reversed by supplementation with α-ketoglutarate. These results reveal that IFNβ modulates macrophage activation and polarization through control of the cellular α-ketoglutarate/succinate ratio.

Original languageEnglish
Article number110719
Number of pages11
JournalCell Reports
Issue number3
Publication statusPublished - 19 Apr 2022
Externally publishedYes


  • CP: Immunology
  • CP: Metabolism
  • granulocyte macrophage colony-stimulating factor
  • interleukin-4
  • isocitrate dehydrogenase
  • macrophage polarization
  • metabolism
  • succinate
  • type I interferon
  • α-ketoglutarate

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