4-Octyl itaconate suppresses IFN-γ-induced MHC II expression in bone marrow-derived macrophages.

Macrophages function as professional antigen-presenting cells that integrate inflammatory signals with metabolic reprogramming to shape immune responses. Itaconate, an immunometabolite derived from ACOD1/IRG1 activity in activated macrophages, has been implicated in the regulation of inflammatory responses, yet its role in interferon γ (IFN-γ)-driven antigen presentation programs remains incompletely understood. Here, we demonstrate that the itaconate derivative 4-octyl itaconate (4-OI) suppresses IFN-γ-induced antigen presentation programs in bone marrow-derived macrophages. 4-OI reduced surface major histocompatibility complex class II (MHC II) expression and downregulated key components of the antigen presentation machinery, including CIITA, H2-Ab1, and H2-Eb1. Transcriptomic analysis revealed broad suppression of IFN-γ-responsive immune pathways, particularly those associated with antigen processing and inflammatory signaling. Mechanistically, 4-OI attenuated IFN-γ-induced phosphorylation of JAK1, JAK2, and STAT1, and pharmacological inhibition of JAK signaling phenocopied its effects on MHC II expression, implicating involvement of the IFN-γ-JAK-STAT1-CIITA axis. In vivo, 4-OI similarly reduced IFN-γ-induced MHC II expression in splenic macrophages, accompanied by decreased PD-L1 expression as a parallel marker of macrophage activation. Together, these findings identify 4-OI as an immunometabolic regulator of IFN-γ-driven macrophage activation, associated with modulation of the JAK-STAT1-CIITA signaling axis and suppression of antigen presentation programs.