Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors

Weiss, Jonathan M.; Davies, Luke; Karwan, Megan; Ileva, Lilia; Ozaki, Michelle K.; Cheng, Robert Y.S.; Ridnour, Lisa A.; Annunziata, Christina M.; Wink, David A.; McVicar, Daniel W.

doi:10.1172/jci99169

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Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors

Jonathan M. Weiss, Luke Davies

, Megan Karwan, Lilia Ileva

, Michelle K. Ozaki, Robert Y.S. Cheng

, Lisa A. Ridnour, Christina M. Annunziata

, David A. Wink, Daniel W. McVicar

Journal of Clinical Investigation, Volume: 128, Issue: 9, Pages: 3794 - 3805

Swansea University Author: Luke Davies

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DOI (Published version): 10.1172/jci99169

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...

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Published in:	Journal of Clinical Investigation
ISSN:	0021-9738 1558-8238
Published:	American Society for Clinical Investigation 2018
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URI:	https://cronfa.swan.ac.uk/Record/cronfa61700
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spelling	2022-11-07T13:36:39.9291156 v2 61700 2022-10-31 Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors ff080296775381560053d5e3a6e81745 0000-0001-7767-4060 Luke Davies Luke Davies true false 2022-10-31 BMS 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. Journal Article Journal of Clinical Investigation 128 9 3794 3805 American Society for Clinical Investigation 0021-9738 1558-8238 31 8 2018 2018-08-31 10.1172/jci99169 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University This research was supported by the Intramural Research Program of the NIH, NCI, CCR. LCD is funded by the Henry Wellcome Trust, United Kingdom (WT103973MA) 2022-11-07T13:36:39.9291156 2022-10-31T12:38:53.0066738 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Jonathan M. Weiss 1 Luke Davies 0000-0001-7767-4060 2 Megan Karwan 3 Lilia Ileva 0000-0001-8286-8396 4 Michelle K. Ozaki 5 Robert Y.S. Cheng 0000-0003-0287-6439 6 Lisa A. Ridnour 7 Christina M. Annunziata 0000-0003-2033-6532 8 David A. Wink 9 Daniel W. McVicar 10 61700__25668__ed626a26a09b4b1eafdde444237a07b7.pdf 61700.pdf 2022-11-07T13:35:32.4966465 Output 2865800 application/pdf Version of Record true This work is licensed under the Creative Commons Attribution 4.0 International License. true eng http://creativecommons.org/licenses/by/4.0/
title	Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors
spellingShingle	Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors Luke Davies
title_short	Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors
title_full	Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors
title_fullStr	Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors
title_full_unstemmed	Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors
title_sort	Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors
author_id_str_mv	ff080296775381560053d5e3a6e81745
author_id_fullname_str_mv	ff080296775381560053d5e3a6e81745_***_Luke Davies
author	Luke Davies
author2	Jonathan M. Weiss Luke Davies Megan Karwan Lilia Ileva Michelle K. Ozaki Robert Y.S. Cheng Lisa A. Ridnour Christina M. Annunziata David A. Wink Daniel W. McVicar
format	Journal article
container_title	Journal of Clinical Investigation
container_volume	128
container_issue	9
container_start_page	3794
publishDate	2018
institution	Swansea University
issn	0021-9738 1558-8238
doi_str_mv	10.1172/jci99169
publisher	American Society for Clinical Investigation
college_str	Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id	facultyofmedicinehealthandlifesciences
hierarchy_top_title	Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id	facultyofmedicinehealthandlifesciences
hierarchy_parent_title	Faculty of Medicine, Health and Life Sciences
department_str	Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str	1
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description	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.
published_date	2018-08-31T04:20:43Z
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score	10.998093

Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors

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