Autocrine IFN-I inhibits isocitrate dehydrogenase in the TCA cycle of LPS-stimulated macrophages
David P. De Souza, … , John A. Hamilton, Andrew J. Fleetwood
David P. De Souza, … , John A. Hamilton, Andrew J. Fleetwood
Published October 1, 2019; First published September 4, 2019
Citation Information: J Clin Invest. 2019;129(10):4239-4244. https://doi.org/10.1172/JCI127597.
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Categories: 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 2

Autocrine type I IFN controls carbon flow through IDH in LPS-treated macrophages.

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Autocrine type I IFN controls carbon flow through IDH in LPS-treated mac...
13C-glucose labeling of citrate and succinate in (A) BMMs (WT and Ifnar1–/–) stimulated or not with LPS (100 ng/mL, 24 hours) or (B) WT BMMs stimulated with LPS (100 ng/mL, 24 hours) in the presence of IFN-β Ab (50 U/mL) or Ct Ab (250 ng/mL, corresponding to 50 U/mL anti–IFN-β Ab). Cells were treated with 13C-glucose (10 mM) for 24 hours (i.e., labeling was initiated at the time of LPS treatment). 13C incorporation was analyzed by GC-MS. Mean percentage labeling ± SEM (n = 3) is shown. See Supplemental Figure 1, I and J, for 13C-glucose labeling of itaconate. Circle sizes are scaled with respect to pool sizes relative to untreated WT BMMs in A, or to BMMs + LPS + Ct Ab in B, for each metabolite.