Choline Uptake and Metabolism Modulate Macrophage IL-1β and IL-18 Production

Sánchez-López, Elsa; Zhong, Zhenyu; Stubelius, Alexandra; Sweeney, Shannon R.; Booshehri, Laela M.; Antonucci, Laura; Liu‐Bryan, Ru; Lodi, Alessia; Terkeltaub, Robert; Lacal, Juan Carlos; Murphy, Anne N.; Hoffman, Hal M.; Tiziani, Stefano; Gumá, Mónica; Karin, Michael

doi:10.1016/j.cmet.2019.03.011

Cited by 157 publications

(152 citation statements)

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“…Mitochondrial dysfunction or oxidized mitochondrial DNA fragments can also serve as signal for NLRP3 inflammasome activation 50,51 . Similar to our work, a recent paper from Karin lab showed inhibiting choline uptake leads to activation of AMPK and mitophagy and dampening of NLRP3 inflammasome activity and IL-1β release 52 . Miltefosine, a ephosphocholine analogue can inhibit phosphatidylcholine (PC) biosynthesis 53 , thus Miltefosine may be activating AMPK via PC depletion, leading to induced mitophagy and NLRP3 inflammasome inhibition.…”

Section: Discussionsupporting

confidence: 89%

Miltefosine increases macrophage cholesterol release and inhibits NLRP3-inflammasome assembly and IL-1β release

Iacano

Lewis

Hazen

et al. 2018

Preprint

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Miltefosine is an FDA approved oral drug for treating cutaneous and visceral leishmaniasis.Leishmania is a flagellated protozoa, which infects and differentiates in macrophages. Here, we studied the effects of Miltefosine on macrophage's lipid homeostasis, autophagy, and NLRP3 inflammasome assembly/activity. Miltefosine treatment conferred multiple effects on macrophage lipid homeostasis leading to increased cholesterol release from cells, increased lipid-raft disruption, decreased phosphatidylserine (PS) flip from the cell-surface, and redistribution of phosphatidylinositol 4,5-bisphosphate (PIP2) from the plasma membrane to actin rich regions in the cells. Enhanced basal autophagy, lipophagy and mitophagy was observed in cells treated with Miltefosine vs. control. Miltefosine treated cells showed marked increased in phosphorylation of kinases involved in autophagy induction such as; Adenosine monophosphate-activated protein kinase (AMPK) and Unc-51 like autophagy activating kinase (ULK1). The Toll like receptor (TLR) signaling pathway was blunted by Miltefosine treatment, resulting in decreased TLR4 recruitment to cell-surface and ~75% reduction in LPS induced pro-IL-1β mRNA levels. Miltefosine reduced endotoxin-mediated mitochondrial reactive oxygen species and protected the mitochondrial membrane potential. Miltefosine treatment induced mitophagy and dampened NLRP3 inflammasome assembly. Collectively, our data shows that Miltefosine induced ABCA1 mediated cholesterol release, induced AMPK phosphorylation and mitophagy, while dampening NLRP3 inflammasome assembly and IL-1β release.3 Significance Statement:Atherosclerosis is driven by cholesterol accumulation and inflammation, and the arterial macrophage is a key cell type in both of these processes. The macrophage characteristics that protect against atherosclerosis include increased cholesterol efflux/reverse cholesterol transport, increased autophagy, and deceased inflammatory cytokine production and signaling.Here, we show that one single orally available compound, Miltefosine, can target multiple macrophage pathways involved in lipid homeostasis and inflammation. Miltefosine activated cholesterol release and autophagy while inhibiting pro IL-1β gene expression and NLRP3 inflammasome assembly. Miltefosine activated AMPK signaling pathway and mitophagy, leading to reduced NLRP3 inflammasome assembly and IL-1β release.4 Introduction:

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Section: Discussionsupporting

confidence: 89%

Miltefosine increases macrophage cholesterol release and inhibits NLRP3-inflammasome assembly and IL-1β release

Iacano

Lewis

Hazen

et al. 2018

Preprint

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“…The decreases in phosphocholine, glycerophosphocholine, betaine and glycine, observed in AgNP‐treated cells (and to lesser extent in Ag + ‐exposed macrophages) may also be potentially related to the metabolic rewiring described above, namely, to sustain the argininosuccinate shunt and/or creatine production (Figure ). Interestingly, choline uptake and metabolism have recently been linked to activation of macrophage Toll‐like receptors (TLR) , …”

Section: Discussionmentioning

confidence: 99%

Macrophage Metabolomics Reveals Differential Metabolic Responses to Subtoxic Levels of Silver Nanoparticles and Ionic Silver

et al. 2020

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This study employed NMR metabolomics to characterize macrophage responses to subtoxic concentrations of silver nanoparticles (AgNPs ca. 30 nm) and ionic silver (Ag + ), with a view to further elucidate their immunomodulatory activity at the cell metabolism level. Exposure to AgNPs caused RAW 264.7 macrophages to decrease intracellular glucose utilization, possibly due to interference with glycolytic enzymes, and to reprogram the TCA cycle towards anaplerotic fueling and production of anti-inflammatory metabolites (e.g. itaconate and creatine). Moreover, AgNPs-exposed cells were able to control the levels [a] Dr. 1867of reactive oxygen/nitrogen species (ROS/RNS), likely through upregulation of glutathione synthesis. On the other hand, macrophages exposed to Ag + at equivalent subtoxic concentrations showed reduced metabolic activity, lower ability to counterbalance ROS/RNS and alterations in membrane-related lipids. Overall, the metabolomics approach hereby employed provided novel insights into the differential effects of AgNPs and Ag + , which help explain the lower toxic potential of nanosilver than silver ions.ter. Moreover, since the release of silver ions from AgNPs has been highlighted as a main driver of AgNPs toxicity, [23] the metabolic effects of ionic silver (administered as AgNO 3 ), at inhibi-Joana Carrola graduated in Chemistry from the University of Porto, and obtained her PhD in Nanosciences and Nanotechnology, in 2017, from the University of Aveiro. Her PhD research focused on silver nanoparticles metabolism in mammalian cells. She is an expert in metabolomics, with interests in the study of drugs and nanomaterials metabolism.Verónica Bastos obtained her PhD in Biology studying nanotoxicity in in vitro cell cultures at the University of Aveiro, 2016. She is currently a Researcher in a project studying upconversion nanoparticles for multimodal therapy of melanoma at CESAM, Biology department of University of Aveiro. Her main research interests are related to nanotoxicity, nanobiomedicine and cancer therapy, ecotoxicology and human health. Ana Luísa Daniel-da-Silva graduated in Chemical Engineering by Instituto Superior Técnico (Lisbon, Portugal) in 2000 and obtained her PhD degree in Materials Science from the University of Alicante (Spain) in 2005. Since 2009 she is researcher at CICECO-Portugal. Her research focuses on the development of functional nanoparticles and nanocomposites for applications in nanomedicine, bionanotechnology and water remediation. and a member of CICECO-Aveiro Institute of Materials. Her main research interests are: 1) NMR metabolomics of biological systems (biofluids, intact tissues, tissue/material systems, cell cultures) subjected to disease, therapeutics, toxicological or environmental stresses for identification of novel biomarkers; 2) Metabolomic testing of novel biomaterials with applications in biodegradable implants, drug delivery or localized cell recognition; 3) Development of spectroscopy-based methods for food quality control.Conceição Santos is a Full Profes...

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“…Moreover, although we demonstrate evidence for the CTL family as being the main facilitators of choline uptake, the relative contribution of each protein remains unknown. Past studies have used siRNA and antibody occlusion to tease out a primary role for CTL1 in macrophage biology (27,28) ; however, until now such an approach had not been mirrored in hepatocytes. Here we show that in human hepatocytederived Huh7.5 cells, antibody blockage and siR-NA-mediated knockdown of CTL1 is on par with the pan-choline uptake inhibitor HC3.…”

Section: Discussionmentioning

confidence: 99%

Hepatic Choline Transport Is Inhibited During Fatty Acid–Induced Lipotoxicity and Obesity

et al. 2020

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Choline is an essential nutrient and a critical component of the membrane phospholipid phosphatidylcholine (PC), the neurotransmitter acetylcholine, while also contributing to the methylation pathway. In the liver specifically, PC is the major membrane constituent and can be synthesized by the cytidine diphosphate-choline or the phosphatidylethanolamine N-methyltransferase pathway. With the continuing global rise in the rates of obesity and nonalcoholic fatty liver disease, we sought to explore how excess fatty acids on primary hepatocytes and diet-induced obesity affect choline uptake and metabolism. Our results demonstrate that hepatocytes chronically treated with palmitate, but not oleate or a mixture, had decreased choline uptake, which was associated with lower choline incorporation into PC and lower expression of choline transport proteins. Interestingly, a reduction in the rate of degradation spared PC levels in response to palmitate when compared with control. The effects of palmitate treatment were independent of endoplasmic reticulum stress, which counterintuitively augmented choline transport and transporter expression. In a model of obesity-induced hepatic steatosis, male mice fed a 60% high-fat diet for 10 weeks had significantly diminished hepatic choline uptake compared with lean mice fed a control diet. Although the transcript and protein expression of various choline metabolic enzymes fluctuated slightly, we observed reduced protein expression of choline transporter-like 1 (CTL1) in the liver of mice fed a high-fat diet. Polysome profile analyses revealed that in livers of obese mice, the CTL1 transcript, despite being more abundant, was translated to a lesser extent compared with lean controls. Finally, human liver cells demonstrated a similar response to palmitate treatment. Conclusion: Our results suggest that the altered fatty acid milieu seen in obesity-induced fatty liver disease progression may adversely affect choline metabolism, potentially through CTL1, but that compensatory mechanisms work to maintain phospholipid homeostasis. (Hepatology Communications 2020;4:876-889).

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Choline Uptake and Metabolism Modulate Macrophage IL-1β and IL-18 Production

Cited by 157 publications

References 73 publications

Miltefosine increases macrophage cholesterol release and inhibits NLRP3-inflammasome assembly and IL-1β release

Miltefosine increases macrophage cholesterol release and inhibits NLRP3-inflammasome assembly and IL-1β release

Macrophage Metabolomics Reveals Differential Metabolic Responses to Subtoxic Levels of Silver Nanoparticles and Ionic Silver

Hepatic Choline Transport Is Inhibited During Fatty Acid–Induced Lipotoxicity and Obesity

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