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

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 7

IRG1 is expressed in monocytes associated with human peritoneal tumors.

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IRG1 is expressed in monocytes associated with human peritoneal tumors....
IRG1 expression was evaluated by qPCR using total RNA isolated from cell fractions from 11 human patients with ovarian carcinoma. (A) IRG1 expression levels were established by setting normal PBMC values to 1.0, and the relative levels in ascites monocytes were graphed in relation to the total number of CD45+CD14+ monocytes in each sample. Linear regression analysis was performed (GraphPad Prism) to obtain the best curve fit (r2 = 0.93; P < 0.0001). (B) The fold difference in IRG1 expression among monocytes and non-monocyte fractions is shown. CD14+ monocytes were purified as described in Methods. For each patient sample, the level of IRG1 expression in the non-monocyte fraction was set to 1.0, and the relative level of IRG1 expression in the corresponding monocyte fraction was graphed (log10). Significance was determined by a 1-sample Student’s t test using 1.0 as a theoretical mean (P < 0.05). (C) IRG1 expression levels in CD14+ PBMCs isolated from 6 healthy volunteers and 5 patients were compared with IRG1 levels in the 11 ascites samples. *P < 0.0 and **P < 0.01, by ANOVA corrected for multiple comparisons. (D) IRG1 protein expression in CD14+ monocytes isolated from healthy blood and patients’ ascites was analyzed by Western blotting.