Type I interferon antagonism of the JMJD3-IRF4 pathway modulates macrophage activation and polarization.
Cell Rep
; 39(3): 110719, 2022 04 19.
Article
en En
| MEDLINE
| ID: mdl-35443173
ABSTRACT
Metabolic adaptations can directly influence the scope and scale of macrophage activation and polarization. Here we explore the impact of type I interferon (IFNß) on macrophage metabolism and its broader impact on cytokine signaling pathways. We find that IFNß simultaneously increased the expression of immune-responsive gene 1 and itaconate production while inhibiting isocitrate dehydrogenase activity and restricting α-ketoglutarate accumulation. IFNß also increased the flux of glutamine-derived carbon into the tricarboxylic acid cycle to boost succinate levels. Combined, we identify that IFNß controls the cellular α-ketoglutarate/succinate ratio. We show that by lowering the α-ketoglutarate/succinate ratio, IFNß potently blocks the JMJD3-IRF4-dependent pathway in GM-CSF and IL-4 activated macrophages. The suppressive effects of IFNß 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 IFNß modulates macrophage activation and polarization through control of the cellular α-ketoglutarate/succinate ratio.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Interferón Tipo I
/
Activación de Macrófagos
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Cell Rep
Año:
2022
Tipo del documento:
Article
País de afiliación:
Australia