Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection
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ABSTRACT:
PROVIDER: PRJNA989576 | ENA |
REPOSITORIES: ENA
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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.
2023-07-10 | GSE236252 | GEO
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 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.
| S-EPMC10553840 | biostudies-literature
Project description:Polarization of macrophages to M1 or M2 cells is important for mounting responses against bacterial and helminth infection respectively. Jumonji domain containing 3 (JMJD3), a histone 3 K27 demethylase, has been implicated in the activation of macrophages. Here we show that JMJD3 is essential for M2 macrophage polarization to helminth infection and chitin, though JMJD3 is dispensable for M1 responses. Furthermore, Jmjd3 is critical for proper bone marrow macrophage differentiation in a demethylase activity-dependent manner. Jmjd3 deficiency affected trimethylation of H3K27 in only a limited numbers of genes. Among them, we identified Irf4 as the target transcription factor critical for controlling M2 macrophage polarization. Collectively, these results show that JMJD3-mediated H3K27 demethylation is critical for regulating M2 macrophage development leading to anti-helminth host responses. This SuperSeries is composed of the SubSeries listed below.
2010-08-22 | GSE23306 | GEO
Project description:The RELMα+ macrophage phenotype associates with the presence of anti-inflammatory macrophages and work in other model systems has demonstrated that the balance of pro-inflammatory and anti-inflammatory macrophages is critically important in enabling the resolution of inflammation. Moreover, in the context of type 2 immunity, RELMα+ anti-inflammatory macrophages are associated with the activation of macrophages via the IL4Ra. Despite a breadth of inflammatory pathologies associated with the large intestine, including those that accompany parasitic infection, it is not known about how large intestinal macrophages are activated towards an anti-inflammatory phenotype.
2021-11-15 | E-MTAB-10501 | biostudies-arrayexpress
Project description:The obesity incidence is increasing worldwide with the urgent need to identify new therapeutics. Sex differences in immune cell activation drive obesity-mediated pathologies where males are more susceptible to comorbidities with exacerbated inflammation, and females are protected. The focus of this study was to identify sex-specific immune effectors that regulate obesity pathogenesis, focusing on the M2 macrophage signature gene, Resistin-like molecule α (RELMα). Here we performed single cell RNA-sequencing (scRNA-seq) on visceral adipose tissue stromal vascular fraction on wildtype and RELMα knock-out animals, both males and females, on high fat diet. We utilized the 10x Genomics 3’ CellPlex platform, to label cells with cell multiplexing oligos (CMOs) per sample in each group prior to pooling for downstream barcoding and library construction. This study revealed sex-specific and RELMα-dependent cellular targets and population differences of female and RELMα-mediated protection.
2023-01-12 | GSE219119 | GEO
Project description: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.
2021-07-09 | GSE174606 | GEO
Project description:Choline and methionine/choline deficient diets are widely used to generate severe rodent hepatic steatosis and steatohepatitis in an attempt to reflect stages of human non-alcoholic fatty liver disease (NAFLD). The underlying mechanism of hepatic injury in these models, and how this reflects human disease remains incompletely understood. We used detailed transcriptional analysis to interrogate the molecular mechanisms of this intervention and its similarity to human disease. Adult C57Bl/6J mice were maintained on control, choline deficient (CDD) or methionine/choline deficient (MCDD) diets for 4 weeks. Isolated liver RNA was used for transcriptional profiling by micro array analysis.
2016-06-01 | E-MTAB-3943 | biostudies-arrayexpress
Project description:Goal: To examine the effects of human resistin during helminth infection. Methodology: To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene along with its entire regulatory region (hRetnTg+). Following infection with the helminth Nippostrongylus brasiliensis, whole lung RNA was sequenced in hRetnTg+ mice, control hRetnTg- and naïve mice. Conclusion: In hRetnTg+ mice, many genes involved in inflammation and the immune system, specifically toll-like receptor signaling and chemokines, are significantly upregulated, suggesting that human resistin promotes TLR signaling and inflammation during helminth infection. Examination of whole lung mRNA from Nippostrongylus brasiliensis-infected lungs at day 7 in mice expressing human resistin
2014-11-14 | E-GEOD-60537 | biostudies-arrayexpress
Project description:To explore the influence of maternal choline intake on placental gene expression, we employed whole genome microarray expression profiling to identify genes that were differentially expressed in placental tissues obtained from women consuming two different doses (480 vs. 930 mg/d) of choline throughout the third trimester of pregnancy. Healthy third trimester (gestational week 26-29) pregnant women were randomized to a 12-week choline controlled feeding study. The participants consumed either 480 (n=6) or 930 (n=6) mg choline/d. Full thickness placental samples were collected at delivery to extract RNA and perform the arrays. Healthy third trimester (gestational week 26-29) pregnant women were randomized to a 12-week choline controlled feeding study. The participants consumed either 480 (n=6) or 930 (n=6) mg choline/d for 12 weeks. Placental samples were obtained at delivery
2012-07-12 | E-GEOD-39290 | biostudies-arrayexpress
Project description:The goal of this study was to define the regulation of Tfh cell response during intestinal helminth infection. Using the helminth Trichuris muris, we performed RNA-seq analysis on Tfh cells that develop during acute vs chronic helminth infection. We found that the transcriptomic profile of acute vs chronic induced Tfh cells are distinct and they express Th2/Th1-associated genes, respectively.
2021-10-20 | GSE185992 | GEO