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

doi:10.1016/j.celrep.2022.110719

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

Cell Rep. 2022 Apr 19;39(3):110719. doi: 10.1016/j.celrep.2022.110719.

Affiliations

¹ The Department of Medicine, University of Melbourne, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia.
² Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, Parkville, VIC 3052 Australia.
³ Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3086, Australia.
⁴ Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
⁵ The Department of Medicine, University of Melbourne, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia; Department of Biochemistry and Molecular Biology, Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, VIC 3050, Australia.
⁶ Hudson Institute of Medical Research, Clayton, VIC 3168, Australia.
⁷ The Department of Medicine, University of Melbourne, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia; Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St. Albans, VIC 3021, Australia.
⁸ The Department of Medicine, University of Melbourne, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia; Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia. Electronic address: andrew.fleetwood@baker.edu.au.

PMID: 35443173
DOI: 10.1016/j.celrep.2022.110719

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.

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

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Granulocyte-Macrophage Colony-Stimulating Factor / genetics
Interferon Type I*
Ketoglutaric Acids / metabolism
Ketoglutaric Acids / pharmacology
Macrophage Activation*
Succinic Acid

Substances

Interferon Type I
Ketoglutaric Acids
Granulocyte-Macrophage Colony-Stimulating Factor
Succinic Acid