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

Elsa Sanchez-Lopez, Zhenyu Zhong, Alexandra Stubelius, Shannon R. Sweeney, Laela M. Booshehri, Laura Antonucci, Ru Liu-Bryan, Alessia Lodi, Robert Terkeltaub, Juan Carlos Lacal, Anne N. Murphy, Hal M. Hoffman, Stefano Tiziani, Monica Guma, Michael Karin

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Choline is a vitamin-like nutrient that is taken up via specific transporters and metabolized by choline kinase, which converts it to phosphocholine needed for de novo synthesis of phosphatidylcholine (PC), the main phospholipid of cellular membranes. We found that Toll-like receptor (TLR) activation enhances choline uptake by macrophages and microglia through induction of the choline transporter CTL1. Inhibition of CTL1 expression or choline phosphorylation attenuated NLRP3 inflammasome activation and IL-1β and IL-18 production in stimulated macrophages. Mechanistically, reduced choline uptake altered mitochondrial lipid profile, attenuated mitochondrial ATP synthesis, and activated the energy sensor AMP-activated protein kinase (AMPK). By potentiating mitochondrial recruitment of DRP1, AMPK stimulates mitophagy, which contributes to termination of NLRP3 inflammasome activation. Correspondingly, choline kinase inhibitors ameliorated acute and chronic models of IL-1β-dependent inflammation. Sanchez-Lopez et al. have found that inhibition of choline uptake and phosphorylation in activated macrophages prevent NLRP3 inflammasome activation and IL-1β and IL-18 production. Inhibition of choline incorporation into phosphatidylcholine in the mitochondrial membranes and decreased ATP synthase activity lead to enhanced AMPK-dependent mitophagy that prevents acute and chronic inflammation.

Original languageEnglish (US)
Pages (from-to)1350-1362.e7
JournalCell Metabolism
Volume29
Issue number6
DOIs
StatePublished - Jun 4 2019

Keywords

  • AMPK
  • CTL1
  • IL-18
  • IL-1β
  • NLRP3
  • choline
  • choline kinase
  • macrophages
  • mitochondrial lipids
  • mitophagy
  • phosphocholine

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Sanchez-Lopez, E., Zhong, Z., Stubelius, A., Sweeney, S. R., Booshehri, L. M., Antonucci, L., Liu-Bryan, R., Lodi, A., Terkeltaub, R., Lacal, J. C., Murphy, A. N., Hoffman, H. M., Tiziani, S., Guma, M., & Karin, M. (2019). Choline Uptake and Metabolism Modulate Macrophage IL-1β and IL-18 Production. Cell Metabolism, 29(6), 1350-1362.e7. https://doi.org/10.1016/j.cmet.2019.03.011