Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection.
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-09-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011658&type=printable |
| _version_ | 1797304769983807488 |
|---|---|
| author | Peyman Ghorbani Sang Yong Kim Tyler K T Smith Lucía Minarrieta Victoria Robert-Gostlin Marisa K Kilgour Maja Ilijevska Irina Alecu Shayne A Snider Kaitlyn D Margison Julia R C Nunes Daniel Woo Ciara Pember Conor O'Dwyer Julie Ouellette Pavel Kotchetkov Julie St-Pierre Steffany A L Bennett Baptiste Lacoste Alexandre Blais Meera G Nair Morgan D Fullerton |
| author_facet | Peyman Ghorbani Sang Yong Kim Tyler K T Smith Lucía Minarrieta Victoria Robert-Gostlin Marisa K Kilgour Maja Ilijevska Irina Alecu Shayne A Snider Kaitlyn D Margison Julia R C Nunes Daniel Woo Ciara Pember Conor O'Dwyer Julie Ouellette Pavel Kotchetkov Julie St-Pierre Steffany A L Bennett Baptiste Lacoste Alexandre Blais Meera G Nair Morgan D Fullerton |
| author_sort | Peyman Ghorbani |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T00:15:15Z |
| format | Article |
| id | doaj.art-90d98c83331e4ab19bdf970a30da6155 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-03-08T00:15:15Z |
| publishDate | 2023-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-90d98c83331e4ab19bdf970a30da61552024-02-17T05:31:51ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742023-09-01199e101165810.1371/journal.ppat.1011658Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection.Peyman GhorbaniSang Yong KimTyler K T SmithLucía MinarrietaVictoria Robert-GostlinMarisa K KilgourMaja IlijevskaIrina AlecuShayne A SniderKaitlyn D MargisonJulia R C NunesDaniel WooCiara PemberConor O'DwyerJulie OuellettePavel KotchetkovJulie St-PierreSteffany A L BennettBaptiste LacosteAlexandre BlaisMeera G NairMorgan D FullertonType 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.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011658&type=printable |
| spellingShingle | Peyman Ghorbani Sang Yong Kim Tyler K T Smith Lucía Minarrieta Victoria Robert-Gostlin Marisa K Kilgour Maja Ilijevska Irina Alecu Shayne A Snider Kaitlyn D Margison Julia R C Nunes Daniel Woo Ciara Pember Conor O'Dwyer Julie Ouellette Pavel Kotchetkov Julie St-Pierre Steffany A L Bennett Baptiste Lacoste Alexandre Blais Meera G Nair Morgan D Fullerton Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection. PLoS Pathogens |
| title | Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection. |
| title_full | Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection. |
| title_fullStr | Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection. |
| title_full_unstemmed | Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection. |
| title_short | Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection. |
| title_sort | choline metabolism underpins macrophage il 4 polarization and relmα up regulation in helminth infection |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011658&type=printable |
| work_keys_str_mv | AT peymanghorbani cholinemetabolismunderpinsmacrophageil4polarizationandrelmaupregulationinhelminthinfection AT sangyongkim cholinemetabolismunderpinsmacrophageil4polarizationandrelmaupregulationinhelminthinfection AT tylerktsmith cholinemetabolismunderpinsmacrophageil4polarizationandrelmaupregulationinhelminthinfection AT luciaminarrieta cholinemetabolismunderpinsmacrophageil4polarizationandrelmaupregulationinhelminthinfection AT victoriarobertgostlin cholinemetabolismunderpinsmacrophageil4polarizationandrelmaupregulationinhelminthinfection AT marisakkilgour cholinemetabolismunderpinsmacrophageil4polarizationandrelmaupregulationinhelminthinfection AT majailijevska cholinemetabolismunderpinsmacrophageil4polarizationandrelmaupregulationinhelminthinfection AT irinaalecu cholinemetabolismunderpinsmacrophageil4polarizationandrelmaupregulationinhelminthinfection AT shayneasnider cholinemetabolismunderpinsmacrophageil4polarizationandrelmaupregulationinhelminthinfection AT kaitlyndmargison cholinemetabolismunderpinsmacrophageil4polarizationandrelmaupregulationinhelminthinfection AT juliarcnunes cholinemetabolismunderpinsmacrophageil4polarizationandrelmaupregulationinhelminthinfection AT danielwoo cholinemetabolismunderpinsmacrophageil4polarizationandrelmaupregulationinhelminthinfection AT ciarapember cholinemetabolismunderpinsmacrophageil4polarizationandrelmaupregulationinhelminthinfection AT conorodwyer cholinemetabolismunderpinsmacrophageil4polarizationandrelmaupregulationinhelminthinfection AT julieouellette cholinemetabolismunderpinsmacrophageil4polarizationandrelmaupregulationinhelminthinfection AT pavelkotchetkov cholinemetabolismunderpinsmacrophageil4polarizationandrelmaupregulationinhelminthinfection AT juliestpierre cholinemetabolismunderpinsmacrophageil4polarizationandrelmaupregulationinhelminthinfection AT steffanyalbennett cholinemetabolismunderpinsmacrophageil4polarizationandrelmaupregulationinhelminthinfection AT baptistelacoste cholinemetabolismunderpinsmacrophageil4polarizationandrelmaupregulationinhelminthinfection AT alexandreblais cholinemetabolismunderpinsmacrophageil4polarizationandrelmaupregulationinhelminthinfection AT meeragnair cholinemetabolismunderpinsmacrophageil4polarizationandrelmaupregulationinhelminthinfection AT morgandfullerton cholinemetabolismunderpinsmacrophageil4polarizationandrelmaupregulationinhelminthinfection |