Autocrine IFN-I inhibits isocitrate dehydrogenase in the TCA cycle of LPS-stimulated macrophages
David P. De Souza, Adrian Achuthan, Man K.S. 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
David P. De Souza, Adrian Achuthan, Man K.S. 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
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Concise Communication Inflammation Metabolism

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

Authors

David P. De Souza, Adrian Achuthan, Man K.S. 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

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Figure 1

Autocrine type I IFN promotes TCA cycle fragmentation and citrate accumulation in LPS-treated macrophages.

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Autocrine type I IFN promotes TCA cycle fragmentation and citrate accumu...
Metabolic profiling of WT and Ifnar1–/– BMMs stimulated or not with LPS (100 ng/mL) for 24 hours was carried out by GC-MS. (A) Schematic diagram of the TCA cycle, with the abundance of individual metabolites quantified. Data (fold change) are presented as histograms (n = 6). Gene and protein levels of Irg1 were determined by qPCR (n = 4) and Western blot analysis. (B) Citrate, aconitate, itaconate, and α-ketoglutarate levels determined by GC-MS in WT BMMs stimulated with LPS (100 ng/mL, 24 hours) in the presence of 50 U/mL of an IFN-β–neutralizing Ab or isotype control IgG (250 ng/mL, corresponding to 50 U/mL IFN-β Ab). P values were determined by 1-way ANOVA (A) or Student’s t test (B). α-KG, α-ketoglutarate; Ct, control.