4.8 Article

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

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CELL REPORTS
卷 39, 期 3, 页码 -

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CELL PRESS
DOI: 10.1016/j.celrep.2022.110719

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  1. University of Melbourne [1159901]
  2. NHMRC

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

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