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J Clin Invest. 2019 Oct 1;129(10):4239-4244. doi: 10.1172/JCI127597.

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

Author information

1
Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia.
2
Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria, Australia.
3
Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
4
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia.
5
Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
6
Australian Institute for Musculoskeletal Science (AIMSS), University of Melbourne and Western Health, St. Albans, Victoria, Australia.

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.

KEYWORDS:

Cellular immune response; Inflammation; Macrophages; Metabolism; Mitochondria

PMID:
31483287
DOI:
10.1172/JCI127597
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