Dynamic crosstalk between fatty acid ß-oxidation and Type 1 interferon immune responsiveness in myeloid cells 3016

Description Cellular metabolism plays a key role in shaping immune cell function, with recent studies linking fatty acid oxidation (FAO) to innate immunity. Here, we show that activating the STING pathway with DMXAA enhances FAO in bone marrow-derived macrophages (BMDMs), an effect mirrored by IFN-β treatment. This increase in FAO correlates with elevated levels of key FAO enzymes: CPT1a and ACAT1. Depleting CPT1a in BMDMs blunted FAO and disrupted IFN-β production with reduced STAT1, STAT2, IRF-3, and IFN-β expression. This was linked to decreased H3K9/K14 acetylation, confirming FAO’s role in sustaining the type 1 interferon (T1IFN) response T1IFN-stimulated FAO was dynamic as higher IFN-β concentrations significantly reduced FAO and FAO enzyme levels, suggesting a negative feedback loop. This could be attributed to increased levels of interferon-stimulated gene 15 (ISG15), known to modify protein stability by ISGylation. In ISG15 knockout BMDMs, FAO was enhanced as suggested by the increased basal oxygen consumption rate and FAO enzyme levels along with increased T1IFN activity. Furthermore, Co-IP experiments showed ISGylation of CPT1a and ACAT1 in DMXAA-treated BMDMs. Together, these findings indicate that T1IFN enhances FAO to regulate IFN production in a feedforward manner, while at higher concentrations, T1IFN induces ISG15, which ISGylates key FAO enzymes, thereby decreasing FAO and T1IFN response through feedback inhibition to maintain immune homeostasis. Funding Sources The work was funded by NHLBI Division of Intramural Research (Grant number – HL005102).