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 6

pResMϕ regulate MAPK activation in peritoneal tumors via itaconate and ROS.

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pResMϕ regulate MAPK activation in peritoneal tumors via itaconate and R...
B16 tumor lysates were prepared as described in Methods and analyzed by Western blotting for expression of p-ERK and total ERK. (A) Tumor lysates from mice that received scrambled or Irg1 shRNA constructs were compared (n ≥4). *P < 0.05, by Mann-Whitney U test. (B) Tumor lysates from mice that received control or clodronate liposomes were compared. *P < 0.05, by Mann-Whitney U test. (C) Tumor lysates from saline control– or NAC-treated mice were analyzed (n = 5). *P < 0.05, by Mann-Whitney U test. (D) NAC i.p. treatment reduced the number of B16 tumor cells (n = 10). **P < 0.01, by Mann-Whitney U test. (E) B16 tumor cells were cultured in vitro alone or in coculture with the indicated pResMϕ. After 48 hours, tumor cells, gated by CD146+F4/80– expression, were analyzed by flow cytometry for intracellular p-ERK expression. *P < 0.05 and **P < 0.01, by ANOVA, corrected for multiple comparisons. Data represent the mean ± SEM.