Type 1 interferons induce changes in core metabolism that are critical for immune function

Type 1 interferons (IFNs) induce complex responses that can be beneficial or deleterious, depending on context. Greater understanding of the mechanisms of action of these cytokines could allow new therapeutic approaches. We found that type 1 IFNs induced changes in cellular metabolism that were critical for changes in target cell function. This was apparent in plasmacytoid dendritic cells, which are specialized for type 1 IFN production, where toll-like receptor-9 (TLR9)-dependent activation was found to be dependent on increased fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) induced by autocrine signaling through the type 1 IFN receptor (IFNAR). Type 1 IFNs also induced FAO/OXPHOS in non-hematopoietic cells and were found to be responsible for increased FAO/OXPHOS in virus-infected cells. Increased FAO/OXPHOS in response to IFNAR signaling was regulated by the nuclear receptor PPARα. Our findings reveal PPARα/FAO/OXPHOS as potential targets to therapeutically modulate downstream effects of type 1 IFNs. mRNA profiles of overnight stimulated plasmacytoid dendritic cells, activated with CpG or INFa. Samples analyzed in triplicate, with HiSeq 2500 by’/ 50bpX25bp pair-end sequencing