Biochemistry and Pharmacology - Research Publications

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

Lee, KM-C ; Achuthan, AA ; De Souza, DP ; Lupancu, TJ ; Binger, KJ ; Lee, MKS ; Xu, Y ; McConville, MJ ; de Weerd, NA ; Dragoljevic, D ; Hertzog, PJ ; Murphy, AJ ; Hamilton, JA ; Fleetwood, AJ (CELL PRESS, 2022-04-19)

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.