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Autocrine IFN-I inhibits isocitrate dehydrogenase in the TCA cycle of LPS-stimulated macrophages.

ABSTRACT: 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/?-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 for the inhibition of IDH in LPS-stimulated macrophages.

SUBMITTER: De Souza DP

PROVIDER: S-EPMC6763227 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Autocrine IFN-I inhibits isocitrate dehydrogenase in the TCA cycle of LPS-stimulated macrophages.

De Souza David P DP Achuthan Adrian A Lee Man Ks MK Binger Katrina J KJ Lee Ming-Chin MC Davidson Sophia S Tull Dedreia L DL McConville Malcolm J MJ Cook Andrew D AD Murphy Andrew J AJ Hamilton John A JA Fleetwood Andrew J AJ

The Journal of clinical investigation 20191001 10

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 ...[more]

PMID: 31483287

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| S-EPMC11299938 | biostudies-literature

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