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Macrophage-regulatory T cell interactions promote type 2 immune homeostasis through Resistin-like molecule α

ABSTRACT: RELMα is a small, secreted protein expressed by T helper type 2 (Th2) cytokine activated “M2” macrophages in helminth infection and allergy. At steady state and in response to Th2 cytokines, RELMα is highly expressed by peritoneal macrophages. We generated RELMα TdTomato (Td) reporter/knockout (RΕLMαTd/Td) mice. RELMαTd/Td mice had increased IL-4 induced peritoneal macrophage responses and splenomegaly compared to RELMα+/+ mice. Nanostring data indicated that RELMαTd/Td peritoneal macrophages were more proliferative and activated than RELMα+/+ macrophages, with increased genes associated with T cell response, growth factor and cytokine signaling, but decreased genes associated with differentiation and maintenance of myeloid cells.This studies identify a new RELMα regulatory pathway whereby RELMα-expressing macrophages directly sustain Treg proliferation to limit Th2 inflammatory responses.

ORGANISM(S): Mus musculus

PROVIDER: GSE174606 | GEO | 2021/07/09

REPOSITORIES: GEO

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Project 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 upregulation 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 intestinal helminths Heligmosomoides polygyrus or Nippostrongylus brasiliensis 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, but there were no differences in intestinal worm count nor differences in N. brasiliensis parasite 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.

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Macrophage-regulatory T cell interactions promote type 2 immune homeostasis through Resistin-like molecule α

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