Profound metabolic changes are characteristic of macrophages during classical activation and have been implicated in this phenotype. Here we demonstrate that nitric oxide (NO) produced by murine macrophages is responsible for TCA cycle alterations and citrate accumulation associated with polarization. 13C tracing and mitochondrial respiration experiments map NO-mediated suppression of metabolism to mitochondrial aconitase (ACO2). Moreover, we find that inflammatory macrophages reroute pyruvate away from pyruvate dehydrogenase (PDH) in an NO-dependent and hypoxia-inducible factor 1α (Hif1α)-independent manner, thereby promoting glutamine-based anaplerosis. Ultimately, NO accumulation leads to suppression and loss of mitochondrial electron transport chain (ETC) complexes. Our data reveal that macrophages metabolic rewiring, in vitro and in vivo, is dependent on NO targeting specific pathways, resulting in reduced production of inflammatory mediators. Our findings require modification to current models of macrophage biology and demonstrate that reprogramming of metabolism should be considered a result rather than a mediator of inflammatory polarization.
|State||Published - Dec 1 2020|
Bibliographical noteFunding Information:
We thank Prof. Bernhard Brüne at Goethe-University Frankfurt-Faculty of Medicine for providing Hifα1−/− BMDMs, Jeffrey Subleski (Leukocyte Signaling Section, Cancer & Inflammation Program, National Cancer Institute, Frederick, MD, USA) for its technical assistance and Daniel R. Crooks (Urologic Oncology Branch, National Cancer Institute, Bethesda, MD, USA) for helpful discussions. This research was supported, in part, by the intramural Research Program of the NIH, National Cancer Institute USA, 1U24DK097215-01A1 (to RMH, TWMF, and ANL), and Redox Metabolism Shared Resource(s) of the University of Kentucky Markey Cancer Center (P30CA177558). L.C.D. is funded in part by and the Henry Wellcome Trust, UK (WT103973MA). The content of this publication does not reflect views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization simply endorsement by the U.S.Government.
© 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.
ASJC Scopus subject areas
- Chemistry (all)
- Biochemistry, Genetics and Molecular Biology (all)
- Physics and Astronomy (all)