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Choline transport links macrophage phospholipid metabolism and inflammation.

ABSTRACT: Choline is an essential nutrient that is required for synthesis of the main eukaryote phospholipid, phosphatidylcholine. Macrophages are innate immune cells that survey and respond to danger and damage signals. Although it is well-known that energy metabolism can dictate macrophage function, little is known as to the importance of choline homeostasis in macrophage biology. We hypothesized that the uptake and metabolism of choline are important for macrophage inflammation. Polarization of primary bone marrow macrophages with lipopolysaccharide (LPS) resulted in an increased rate of choline uptake and higher levels of PC synthesis. This was attributed to a substantial increase in the transcript and protein expression of the choline transporter-like protein-1 (CTL1) in polarized cells. We next sought to determine the importance of choline uptake and CTL1 for macrophage immune responsiveness. Chronic pharmacological or CTL1 antibody-mediated inhibition of choline uptake resulted in altered cytokine secretion in response to LPS, which was associated with increased levels of diacylglycerol and activation of protein kinase C. These experiments establish a previously unappreciated link between choline phospholipid metabolism and macrophage immune responsiveness, highlighting a critical and regulatory role for macrophage choline uptake via the CTL1 transporter.

SUBMITTER: Snider SA

PROVIDER: S-EPMC6065184 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Choline transport links macrophage phospholipid metabolism and inflammation.

Snider Shayne A SA Margison Kaitlyn D KD Ghorbani Peyman P LeBlond Nicholas D ND O'Dwyer Conor C Nunes Julia R C JRC Nguyen Thao T Xu Hongbin H Bennett Steffany A L SAL Fullerton Morgan D MD

The Journal of biological chemistry 20180607 29

Choline is an essential nutrient that is required for synthesis of the main eukaryote phospholipid, phosphatidylcholine. Macrophages are innate immune cells that survey and respond to danger and damage signals. Although it is well-known that energy metabolism can dictate macrophage function, little is known as to the importance of choline homeostasis in macrophage biology. We hypothesized that the uptake and metabolism of choline are important for macrophage inflammation. Polarization of primary ...[more]

PMID: 29880645

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Project description:BackgroundHarnessing the power of the immune system by using immune checkpoint inhibitors has resulted in some of the most exciting advances in cancer treatment. The full potential of this approach has, however, not been fully realized for treating many cancers such as pancreatic and breast cancer. Cancer metabolism influences many aspects of cancer progression including immune surveillance. An expanded understanding of how cancer metabolism can directly impact immune checkpoints may allow further optimization of immunotherapy. We therefore investigated, for the first time, the relationship between the overexpression of choline kinase-α (Chk-α), an enzyme observed in most cancers, and the expression of the immune checkpoint PD-L1.MethodsWe used small interfering RNA to downregulate Chk-α, PD-L1, or both in two triple-negative human breast cancer cell lines (MDA-MB-231 and SUM-149) and two human pancreatic ductal adenocarcinoma cell lines (Pa09C and Pa20C). The effects of the downregulation were studied at the genomic, proteomic, and metabolomic levels. The findings were compared with the results obtained by the analysis of public data from The Cancer Genome Atlas Program.ResultsWe identified an inverse dependence between Chk-α and PD-L1 at the genomic, proteomic, and metabolomic levels. We also found that prostaglandin-endoperoxide synthase 2 (COX-2) and transforming growth factor beta (TGF-β) play an important role in this relationship. We independently confirmed this relationship in human cancers by analyzing data from The Cancer Genome Atlas Program.ConclusionsOur data identified previously unknown roles of PD-L1 in cancer cell metabolic reprogramming, and revealed the immunosuppressive increased PD-L1 effect of Chk-α downregulation. These data suggest that PD-L1 regulation of metabolism may be mediated through Chk-α, COX-2, and TGF-β. The observations provide new insights that can be applied to the rational design of combinatorial therapies targeting immune checkpoints and cancer metabolism.

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.

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Choline transport links macrophage phospholipid metabolism and inflammation.

Publications

Choline transport links macrophage phospholipid metabolism and inflammation.

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