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

• Published in: Cell metabolism Vol. 29; no. 6; pp. 1350 - 1362.e7
• Main Authors: Sanchez-Lopez, 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, Guma, Monica, Karin, Michael
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.06.2019
• Subjects: AMPK; Animals; Butanes - pharmacology; Cells, Cultured; choline; Choline - metabolism; Choline - pharmacokinetics; choline kinase; Cryopyrin-Associated Periodic Syndromes - genetics; Cryopyrin-Associated Periodic Syndromes - metabolism; Cryopyrin-Associated Periodic Syndromes - pathology; CTL1; Female; HEK293 Cells; Humans; IL-18; IL-1β; Interleukin-18 - metabolism; Interleukin-1beta - metabolism; Intestinal Absorption - drug effects; Lipopolysaccharides - pharmacology; macrophages; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; mitochondrial lipids; mitophagy; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLRP3; Organic Cation Transport Proteins - genetics; Organic Cation Transport Proteins - metabolism; phosphocholine; Pyridinium Compounds - pharmacology; choline; mitophagy; macrophages; phosphocholine; IL-18; CTL1; NLRP3; AMPK; IL-1β; mitochondrial lipids; choline kinase
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2019.03.011

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. [Display omitted] •LPS stimulates choline uptake and phosphorylation via CTL1 induction•Impaired choline uptake or phosphorylation reduces mitochondrial ATP synthesis•Reduced ATP synthesis leads to AMPK activation and induction of mitophagy•By causing mitophagy, ChoKα inhibition prevents NLRP3-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.