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 4

Irg1 silencing in pResMϕ reduces peritoneal tumor burden.

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Irg1 silencing in pResMϕ reduces peritoneal tumor burden. B16 tumor–bea...
B16 tumor–bearing mice were treated with lentiviral shRNA (scrambled control or Irg1 silencing). (A) Gene expression of Irg1 was evaluated by qPCR (n = 9). (B) B16 tumor burden was quantitated and (C) evaluated by MRI of live tumor-bearing mice (MRI images are representative of 8 mice). (D) Tumor volumes were calculated by computing the tumor area on each plane and multiplying by the thickness of each slice (n = 8). The tumor weight (E) and volume (F) of ID8 ovarian carcinoma–bearing mice were measured (n ≥5). (G) Total numbers of F4/80+ pResMϕ were comparable among 6 scrambled shRNA and Irg1 shRNA recipient mice. Gata6 gene expression by qPCR (H) and protein levels were indistinguishable among scrambled (I) and Irg1 (J) shRNA recipient mice. A similar uptake of lentiviral shRNA was confirmed by EGFP visualization in F4/80+ pResMϕ isolated from mice receiving scrambled (K) or Irg1 (L) shRNA constructs. All FACS plots are representative of at least 6 mice per group. (M) Clodronate-depleted CD45.1 congenic mice (5 mice/group) were inoculated i.p. with peritoneal lavage cells from WT or Irg1–/– mice 1 day prior to tumor inoculation, and the B16 tumor burden was quantitated. Data represent the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by Mann-Whitney U test.