Type I interferon antagonism of the JMJD3-IRF4 pathway modulates macrophage activation and polarization.
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| Abstract |
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.
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| Authors | 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 |
| Journal | Cell reports (Cell Rep) Vol. 39 Issue 3 Pg. 110719 (04 19 2022) ISSN: 2211-1247 [Electronic] United States |
| PMID | 35443173 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved. |
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