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

doi:10.1016/j.cmet.2019.03.011

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.

Authors

Affiliations

¹ Departments of Pharmacology and Pathology, University of California San Diego, La Jolla, CA, 92037, USA.
² Departments of Pharmacology and Pathology, University of California San Diego, La Jolla, CA, 92037, USA; Department of Immunology, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas TX 75390, USA.
³ Division of Rheumatology, Allergy and Immunology, University of California San Diego, La Jolla, CA, 92037, USA.
⁴ Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX, 78723-3092, USA.
⁵ Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA, 92037, USA.
⁶ Division of Rheumatology, Allergy and Immunology, University of California San Diego, La Jolla, CA, 92037, USA; VA San Diego Healthcare System, University of California San Diego, La Jolla, CA, 92037, USA.
⁷ Department of Molecular Biosciences, College of Natural Sciences, The University of Texas at Austin, Austin, TX, 78723-3092, USA; Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX, 78723-3092, USA.
⁸ Translational Oncology, Department of Oncology, Hospital Universitario Fuenlabrada, Instituto de Investigación Sanitaria IdiPAZ, Madrid, Spain.
⁹ Department of Molecular Biosciences, College of Natural Sciences, The University of Texas at Austin, Austin, TX, 78723-3092, USA; Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX, 78723-3092, USA; Department of Pediatrics, Dell Medical School, The University of Texas at Austin, Austin, TX, 78723-3092, USA.
¹⁰ Departments of Pharmacology and Pathology, University of California San Diego, La Jolla, CA, 92037, USA. Electronic address: karinoffice@ucsd.edu.

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding