Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection
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Published:2023-09-25
Issue:9
Volume:19
Page:e1011658
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ISSN:1553-7374
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Container-title:PLOS Pathogens
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language:en
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Short-container-title:PLoS Pathog
Author:
Ghorbani PeymanORCID,
Kim Sang Yong,
Smith Tyler K. T.,
Minarrieta Lucía,
Robert-Gostlin Victoria,
Kilgour Marisa K.ORCID,
Ilijevska Maja,
Alecu Irina,
Snider Shayne A.,
Margison Kaitlyn D.,
Nunes Julia R. C.,
Woo Daniel,
Pember Ciara,
O’Dwyer Conor,
Ouellette Julie,
Kotchetkov Pavel,
St-Pierre JulieORCID,
Bennett Steffany A. L.,
Lacoste Baptiste,
Blais Alexandre,
Nair Meera G.ORCID,
Fullerton Morgan D.ORCID
Abstract
Type 2 cytokines like IL-4 are hallmarks of helminth infection and activate macrophages to limit immunopathology and mediate helminth clearance. In addition to cytokines, nutrients and metabolites critically influence macrophage polarization. Choline is an essential nutrient known to support normal macrophage responses to lipopolysaccharide; however, its function in macrophages polarized by type 2 cytokines is unknown. Using murine IL-4-polarized macrophages, targeted lipidomics revealed significantly elevated levels of phosphatidylcholine, with select changes to other choline-containing lipid species. These changes were supported by the coordinated up-regulation of choline transport compared to naïve macrophages. Pharmacological inhibition of choline metabolism significantly suppressed several mitochondrial transcripts and dramatically inhibited select IL-4-responsive transcripts, most notably, Retnla. We further confirmed that blocking choline metabolism diminished IL-4-induced RELMα (encoded by Retnla) protein content and secretion and caused a dramatic reprogramming toward glycolytic metabolism. To better understand the physiological implications of these observations, naïve or mice infected with the intestinal helminth Heligmosomoides polygyrus were treated with the choline kinase α inhibitor, RSM-932A, to limit choline metabolism in vivo. Pharmacological inhibition of choline metabolism lowered RELMα expression across cell-types and tissues and led to the disappearance of peritoneal macrophages and B-1 lymphocytes and an influx of infiltrating monocytes. The impaired macrophage activation was associated with some loss in optimal immunity to H. polygyrus, with increased egg burden. Together, these data demonstrate that choline metabolism is required for macrophage RELMα induction, metabolic programming, and peritoneal immune homeostasis, which could have important implications in the context of other models of infection or cancer immunity.
Funder
Natural Sciences and Engineering Research Council of Canada
Canadian Institutes of Health Research
National Institute of Allergy and Infectious Diseases
Camille Villeneuve Chair in Cardiovascular Immunometabolism
Canada Research Chairs Teir 1
Natural Sciences and Engineering Research Council
Ministry of Ontario
University of Ottawa Brain and Mind Research Institute
Publisher
Public Library of Science (PLoS)
Subject
Virology,Genetics,Molecular Biology,Immunology,Microbiology,Parasitology