@article{e8eca803a4cc4d20b0e4fbd8a8372ed1,
title = "Choline Uptake and Metabolism Modulate Macrophage IL-1β and IL-18 Production",
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.",
keywords = "AMPK, CTL1, IL-18, IL-1β, NLRP3, choline, choline kinase, macrophages, mitochondrial lipids, mitophagy, phosphocholine",
author = "Elsa Sanchez-Lopez and Zhenyu Zhong and Alexandra Stubelius and Sweeney, {Shannon R.} and Booshehri, {Laela M.} and Laura Antonucci and Ru Liu-Bryan and Alessia Lodi and Robert Terkeltaub and Lacal, {Juan Carlos} and Murphy, {Anne N.} and Hoffman, {Hal M.} and Stefano Tiziani and Monica Guma and Michael Karin",
note = "Funding Information: We thank eBioscience, Cell Signaling Technologies, Santa Cruz Technologies, Thermo Fisher, and Promega for gifts of reagents; Drs. Stuart Lipton and Dorit Trudler for providing primary mouse microglia cells; and Christina Dooka, Lauren A Chang, and Lanchen Qu for technical help. Research was supported by the NIH (R01AI43477 and R37AI043477); NIEHS Superfund basic research program (P42ES010337); The Rotary Coins for Alzheimer's Research Trust Fund (CART Fund) awards to M.K. who is an American Cancer Research Society Professor and holds the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases; an LLS 7005-14 award to T. Kipps and M.K.; VA Research Service Merit Review Awards (I01BX001660) and NIH/NIAMS (P50AR060772) to R.T.; (1I01BX002234) and CymaBay Therapeutics grant to R.L.-B.; an NIH award to H.M.H. (R01DK113592); and NIH awards (R01AR073324 and R03AR068094) to M.G. E.S.-L. was supported by a Sara Borrell fellowship from ISCIII/MICINN. Z.Z. was supported by a Cancer Research Institute Irvington Fellowship, the Prevent Cancer Foundation Board of Directors Research Fund, and the American Association for the Study of Liver Diseases Pinnacle Research Award. L.A. was supported by the International Cancer Research Fellowship (iCARE) and AIRC, co-founded by the European Union. The support for the NMR facility was provided by the University of Texas Health Science Center at San Antonio and NIH/NCI (P30CA54174). E.S.-L. conceived the project, designed, and performed most of the experiments. Z.Z. and L.A. provided assistance with experiments and analyses. A.S. and M.G. performed and analyzed the air pouch model. R.L.-B. provided AMPKα1−/− mice. S.R.S. A.L. and S.T. performed NMR and MS analysis. H.M.H. and L.M.B. provided Nlrp3 mutant mice and performed the MWS mouse model and in vitro experiments. J.C.L. provided ChoKα inhibitors. Z.Z. R.T. R.L-B. J.C.L. A.N.M. H.M.H. M.G. and M.K. provided advice. M.K. supervised the project. E.S.-L. and M.K. wrote the manuscript with input from all authors. The University of California San Diego is in the process of applying for a patent covering the use of CTL1 and/or choline kinase genetic/chemical inhibitors to treat NLRP3 inflammasome-associated diseases listing E.S.-L. and M.K. as inventors. Funding Information: We thank eBioscience, Cell Signaling Technologies, Santa Cruz Technologies, Thermo Fisher, and Promega for gifts of reagents; Drs. Stuart Lipton and Dorit Trudler for providing primary mouse microglia cells; and Christina Dooka, Lauren A Chang, and Lanchen Qu for technical help. Research was supported by the NIH ( R01AI43477 and R37AI043477 ); NIEHS Superfund basic research program ( P42ES010337 ); The Rotary Coins for Alzheimer{\textquoteright}s Research Trust Fund (CART Fund) awards to M.K., who is an American Cancer Research Society Professor and holds the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases; an LLS 7005-14 award to T. Kipps and M.K.; VA Research Service Merit Review Awards ( I01BX001660 ) and NIH/NIAMS ( P50AR060772 ) to R.T.; ( 1I01BX002234 ) and CymaBay Therapeutics grant to R.L.-B.; an NIH award to H.M.H. ( R01DK113592 ); and NIH awards ( R01AR073324 and R03AR068094 ) to M.G. E.S.-L. was supported by a Sara Borrell fellowship from ISCIII/MICINN . Z.Z. was supported by a Cancer Research Institute Irvington Fellowship , the Prevent Cancer Foundation Board of Directors Research Fund , and the American Association for the Study of Liver Diseases Pinnacle Research Award . L.A. was supported by the International Cancer Research Fellowship (iCARE) and AIRC , co-founded by the European Union. The support for the NMR facility was provided by the University of Texas Health Science Center at San Antonio and NIH/NCI ( P30CA54174 ). Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = jun,
day = "4",
doi = "10.1016/j.cmet.2019.03.011",
language = "English (US)",
volume = "29",
pages = "1350--1362.e7",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "6",
}