Autocrine IFN-I inhibits isocitrate dehydrogenase in the TCA cycle of LPS-stimulated macrophages
David P De Souza, Adrian Achuthan, Man KS Lee, Katrina J Binger, Ming-Chin Lee, Sophia Davidson, Dedreia L Tull, Malcolm J McConville, Andrew D Cook, Andrew J Murphy, John A Hamilton, Andrew J Fleetwood
JOURNAL OF CLINICAL INVESTIGATION | AMER SOC CLINICAL INVESTIGATION INC | Published : 2019
Macrophage activation in response to LPS is coupled to profound metabolic changes, typified by accumulation of the TCA cycle intermediates citrate, itaconate, and succinate. We have identified that endogenous type I IFN controls the cellular citrate/α-ketoglutarate ratio and inhibits expression and activity of isocitrate dehydrogenase (IDH); and, via 13C-labeling studies, demonstrated that autocrine type I IFN controls carbon flow through IDH in LPS-activated macrophages. We also found that type I IFN-driven IL-10 contributes to inhibition of IDH activity and itaconate synthesis in LPS-stimulated macrophages. Our findings have identified the autocrine type I IFN pathway as being responsible ..View full abstract
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Awarded by National Health and Medical Research Council (NHMRC)
This work was supported by National Health and Medical Research Council (NHMRC) grants (APP1107001 and APP1159901). MJM is an NHMRC Principal Research Fellow.