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 1

Characterization of peritoneal leukocytes from tumor-bearing hosts.

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Characterization of peritoneal leukocytes from tumor-bearing hosts. Flow...
Flow cytometric analysis was performed on the peritoneal lavage cells from (A) naive and (B) B16 tumor–bearing mice. Among F4/80-sorted leukocytes, Gata6 expression was evaluated by (C) qPCR and (D) intracellular flow cytometry. Flow cytometric plots are representative of 6 samples (2 experiments each consisting of triplicate samples). The dotted lines represent isotype control staining. (E) B16 tumor burden was quantified in WT or Rag–/– mice that received control or clodronate liposomes on day 2 (after tumor) or day 0 (before tumor) (n ≥5). *P < 0.05, **P < 0.01, and ***P < 0.001, by ANOVA with Tukey’s multiple comparisons test. (F) F4/80-sorted Mϕ were evaluated by qPCR for M2 (left) and M1 (right) prototypic gene expression. Triplicate samples were evaluated, with one of the no-tumor samples set to 1.0 as a reference point (heatmaps depict log2-transformed, relative-based results of gene expression; all genes shown were significantly altered in the B16 group to at least P < 0.05 as compared with the no-tumor group; unpaired Student’s t test). Data represent the mean ± SEM.