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 September 4, 2019
Citation Information: J Clin Invest. 2019;129(10):4239-4244. https://doi.org/10.1172/JCI127597.
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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 4

Type I IFN induction of IL-10 contributes to inhibition of IDH.

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Type I IFN induction of IL-10 contributes to inhibition of IDH. (A) Tota...
(A) Total IDH activity in WT BMMs treated with LPS (100 ng/mL, 0–24 hours, n = 6) + IL-10 mAb or control mAb (1 μg/mL). (B) Citrate and (C) aconitate in WT BMMs treated as in A (n = 6). (D) Irg1 gene (n = 6) and (E) protein in WT BMMs treated with LPS (24 hours) + IL-10 mAb or Ct mAb (μg/mL). (F) Itaconate in WT BMMs treated as in A. (G) Total IDH activity in WT BMMs following IL-10 (100 ng/mL) or IFN-β (1000 U/mL, 24 hours, n = 6) treatment. (H) Total IDH activity in WT and Ifnar1–/– BMMs following LPS with or without IL-10 (100 ng/mL, 24 hours, n = 5). (I) Citrate and (J) aconitate in WT and Ifnar1–/– BMMs treated as in H (n = 6). (K) Irg1 gene (n = 6) and (L) protein in WT and Ifnar1–/– BMMs treated as in H. (M) Itaconate in WT and Ifnar1–/– BMMs treated as in H. Mean ± SEM. P values by 1-way ANOVA (A, D, G–K, and M) or Student’s t test (B, C, and F).