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 August 31, 2018; First 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

Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors

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 3

Irg1 and itaconic acid are upregulated in pResMϕ by peritoneal tumors.

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Irg1 and itaconic acid are upregulated in pResMϕ by peritoneal tumors. U...
Unbiased metabolomic analysis was performed on F4/80-sorted pResMϕ from control and either (A) B16 melanoma– or (B) ID8 ovarian carcinoma–bearing mice. The mean values from at least 5 replicate samples were log10 transformed and plotted (P < 0.05 for all metabolites by unpaired Student’s t test). Irg1 gene expression was evaluated by qPCR in F4/80-sorted pResMϕ from control mice and mice bearing either (C) day-9 B16 melanoma, 3LL, or MC38 tumors or (D) day-30 ID8, IG10, or IF5 ovarian carcinomas. Triplicate samples were evaluated, with one of the no-tumor control samples serving as the 1.0 relative reference point. **P < 0.01, by unpaired Student’s t test. (E) IRG1 protein levels in B16 and ID8 tumor lysates and pResMϕ purified from tumors were determined by Western blotting. Unstimulated or LPS-stimulated bone marrow–derived Mϕ from WT and Irg1–/– mice were used as controls. (F) pResMϕ were cocultured in vitro with the indicated tumor cells for 48 hours. Irg1 expression was evaluated by qPCR (n = 3). cocx, co-culture. **P < 0.01 and ****P < 0.0001, by ANOVA with Tukey’s multiple comparisons test. Data represent the mean ± SEM.