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Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors
Jonathan M. Weiss, … , David A. Wink, Daniel W. McVicar
Jonathan M. Weiss, … , David A. Wink, Daniel W. McVicar
Published June 19, 2018
Citation Information: J Clin Invest. 2018;128(9):3794-3805. https://doi.org/10.1172/JCI99169.
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Research Article Metabolism Oncology Article has an altmetric score of 10

Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors

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Abstract

Control of cellular metabolism is critical for efficient cell function, although little is known about the interplay between cell subset–specific metabolites in situ, especially in the tumor setting. Here, we determined how a macrophage-specific (Mϕ-specific) metabolite, itaconic acid, can regulate tumor progression in the peritoneum. We show that peritoneal tumors (B16 melanoma or ID8 ovarian carcinoma) elicited a fatty acid oxidation–mediated increase in oxidative phosphorylation (OXPHOS) and glycolysis in peritoneal tissue–resident macrophages (pResMϕ). Unbiased metabolomics identified itaconic acid, the product of immune-responsive gene 1–mediated (Irg1-mediated) catabolism of mitochondrial cis-aconitate, among the most highly upregulated metabolites in pResMϕ of tumor-bearing mice. Administration of lentivirally encoded Irg1 shRNA significantly reduced peritoneal tumors. This resulted in reductions in OXPHOS and OXPHOS-driven production of ROS in pResMϕ and ROS-mediated MAPK activation in tumor cells. Our findings demonstrate that tumors profoundly alter pResMϕ metabolism, leading to the production of itaconic acid, which potentiates tumor growth. Monocytes isolated from ovarian carcinoma patients’ ascites fluid expressed significantly elevated levels of IRG1. Therefore, IRG1 in pResMϕ represents a potential therapeutic target for peritoneal tumors.

Authors

Jonathan M. Weiss, Luke C. Davies, Megan Karwan, Lilia Ileva, Michelle K. Ozaki, Robert Y.S. Cheng, Lisa A. Ridnour, Christina M. Annunziata, David A. Wink, Daniel W. McVicar

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Figure 2

Tumors increase oxidative and glycolytic metabolism in pResMϕ.

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Tumors increase oxidative and glycolytic metabolism in pResMϕ.
Extracell...
Extracellular flux analysis of F4/80-sorted pResMϕ from non–tumor-bearing control mice or mice inoculated with B16 via the indicated routes were analyzed. The (A) OCR and (B) ECAR were graphed over time as indicators of OXPHOS and glycolysis, respectively. Drugs were injected into the ports at the indicated time points. F4/80-sorted pResMϕ from no–tumor-bearing control mice or mice bearing ID8 ovarian carcinoma (day 47) were similarly evaluated for (C) cellular OCR and (D) ECAR. (E) OXPHOS of peritoneal Mϕ from control and B16 tumor–bearing mice were evaluated following injection of etomoxir into the first port at the indicated time point. (F) Basal OCRs for the treatment groups were graphed. **P < 0.01, by ANOVA with Tukey’s multiple comparisons test. All plots are representative of 3 experiments. Data represent the mean ± SEM. AA, Antimycin A.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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