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

Cell Metab. 2019 Jun 4;29(6):1350-1362.e7. doi: 10.1016/j.cmet.2019.03.011. Epub 2019 Apr 11.

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.

Keywords: AMPK; CTL1; IL-18; IL-1β; NLRP3; choline; choline kinase; macrophages; mitochondrial lipids; mitophagy; phosphocholine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Butanes / pharmacology
  • Cells, Cultured
  • Choline / metabolism*
  • Choline / pharmacokinetics*
  • Cryopyrin-Associated Periodic Syndromes / genetics
  • Cryopyrin-Associated Periodic Syndromes / metabolism
  • Cryopyrin-Associated Periodic Syndromes / pathology
  • Female
  • HEK293 Cells
  • Humans
  • Interleukin-18 / metabolism*
  • Interleukin-1beta / metabolism*
  • Intestinal Absorption / drug effects
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • Organic Cation Transport Proteins / genetics
  • Organic Cation Transport Proteins / metabolism
  • Pyridinium Compounds / pharmacology

Substances

  • 1,4-(4-4'-Bis-((4-(dimethylamine)pyridinium-1-yl) methyl)diphenyl)butane dibromide
  • Butanes
  • CTL1 protein, mouse
  • Interleukin-18
  • Interleukin-1beta
  • Lipopolysaccharides
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Organic Cation Transport Proteins
  • Pyridinium Compounds
  • Choline