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.

NRF2 Activation in Cancer: From DNA to Protein

“…In addition, it was recently reported that the mitochondrial metabolite itaconate activates NRF2-dependent transcription through alkylation of KEAP1 on C151, C257, C273, C288, and C297. Although a role for itaconate has been identified in peritoneal tumors, studies examining the interplay between itaconate, KEAP1, and NRF2 hyperactivation in cancer have not yet been reported (110,111). Recently, Bollong and colleagues identified a new PTM for KEAP1, methylimidazole crosslink between proximal cysteine and arginine residues (MICA; ref.…”

Tricarboxylic acid cycle metabolites in the control of macrophage activation and effector phenotypes

“…A very recent study into the role of IRG1 and itaconate in tumor progression revealed that IRG1 promotes tumor progression through crosstalk between macrophages and tumor cells . In a cancer setting, IRG1 was shown to promote macrophage‐derived mitochondrial ROS which amplifies mitogen‐activated protein kinase (MAPK) activation in a paracrine fashion in neighboring tumor cells.…”

“…A very recent study into the role of IRG1 and itaconate in tumor progression revealed that IRG1 promotes tumor progression through crosstalk between macrophages and tumor cells. 72 In a cancer setting, IRG1 was shown to promote macrophage-derived mitochondrial ROS which amplifies mitogen-activated protein kinase (MAPK) activation in a paracrine fashion in neighboring tumor cells. While this finding that IRG1, and presumably itaconate, promote macrophage mitochondrial ROS is in agreement with a previous study, 73 they are in apparent contradiction with other studies where itaconate was found to actively suppress mitochondrial ROS.…”

Diversity and environmental adaptation of phagocytic cell metabolism

“…Tissues such as the peritoneal cavity are frequently the site of tumor development and metastasis, and as such there is considerable potential crosstalk between developing tumors and tissue‐resident macrophages that normally play important roles in homeostasis and immune surveillance. We recently showed that crosstalk between tumor cells and resident macrophages of the peritoneum induces metabolic alterations in the resident macrophage population, which in turn regulates macrophage effector function and tumor progression . In ovarian carcinoma, which metastasizes to and grows progressively in the peritoneum, altered metabolite expression is highlighted by the dramatic up‐regulation of the metabolite, itaconic acid, in resident macrophages .…”

“…We recently showed that crosstalk between tumor cells and resident macrophages of the peritoneum induces metabolic alterations in the resident macrophage population, which in turn regulates macrophage effector function and tumor progression . In ovarian carcinoma, which metastasizes to and grows progressively in the peritoneum, altered metabolite expression is highlighted by the dramatic up‐regulation of the metabolite, itaconic acid, in resident macrophages . Itaconic acid was already recognized as an important metabolite due to its ability to inhibit the glyoxylate shunt, an anabolic variation of the TCA that is essential for bacterial growth .…”