%0 Journal Article
%T Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors
%A Christina M. Annunziata
%A Daniel W. McVicar
%A David A. Wink
%A Jonathan M. Weiss
%A Lilia Ileva
%A Lisa A. Ridnour
%A Luke C. Davies
%A Megan Karwan
%A Michelle K. Ozaki
%A Robert Y.S. Cheng
%J The Journal of Clinical Investigation
%D 2018
%R 10.1172/JCI99169
%X Control of cellular metabolism is critical for efficient cell function, although little is known about the interplay between cell subset¨Cspecific metabolites in situ, especially in the tumor setting. Here, we determined how a macrophage-specific (M£¿-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¨Cmediated increase in oxidative phosphorylation (OXPHOS) and glycolysis in peritoneal tissue¨Cresident macrophages (pResM£¿). Unbiased metabolomics identified itaconic acid, the product of immune-responsive gene 1¨Cmediated (Irg1-mediated) catabolism of mitochondrial cis-aconitate, among the most highly upregulated metabolites in pResM£¿ 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 pResM£¿ and ROS-mediated MAPK activation in tumor cells. Our findings demonstrate that tumors profoundly alter pResM£¿ 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 pResM£¿ represents a potential therapeutic target for peritoneal tumors
%U https://www.jci.org/articles/view/99169