title: Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages.
abstract: Alternative (M2) activation of macrophages driven via the α-chain of the receptor for interleukin 4 (IL-4Rα) is important for immunity to parasites, wound healing, the prevention of atherosclerosis and metabolic homeostasis. M2 polarization is dependent on fatty acid oxidation (FAO), but the source of the fatty acids that support this metabolic program has not been clear. We found that the uptake of triacylglycerol substrates via the scavenger receptor CD36 and their subsequent lipolysis by lysosomal acid lipase (LAL) was important for the engagement of elevated oxidative phosphorylation, enhanced spare respiratory capacity (SRC), prolonged survival and expression of genes that together define M2 activation. Inhibition of lipolysis suppressed M2 activation during infection with a parasitic helminth and blocked protective responses to this pathogen. Our findings delineate a critical role for cell-intrinsic lysosomal lipolysis in M2 activation.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Stanley Ching-Cheng
authors.initials: SC
authors.lastname: Huang
authors.affiliation: 1] Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA. [2].
authors.forename: Bart
authors.initials: B
authors.lastname: Everts
authors.affiliation: 1] Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA. [2].
authors.forename: Yulia
authors.initials: Y
authors.lastname: Ivanova
authors.affiliation: 1] Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA. [2].
authors.forename: David
authors.initials: D
authors.lastname: O'Sullivan
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Marcia
authors.initials: M
authors.lastname: Nascimento
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Amber M
authors.initials: AM
authors.lastname: Smith
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Wandy
authors.initials: W
authors.lastname: Beatty
authors.affiliation: Department of Medicine and Cell Biology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Latisha
authors.initials: L
authors.lastname: Love-Gregory
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Wing Y
authors.initials: WY
authors.lastname: Lam
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: O'Neill
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indiana, USA.
authors.forename: Cong
authors.initials: C
authors.lastname: Yan
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indiana, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Du
authors.affiliation: Department of Medicine and Cell Biology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Nada A
authors.initials: NA
authors.lastname: Abumrad
authors.affiliation: US Department of Agriculture, Agriculture Research Service, Beltsville Human Nutrition Research Center, Diet, Genomics and Immunology Laboratory, Beltsville, Maryland, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Urban
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Maxim N
authors.initials: MN
authors.lastname: Artyomov
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Erika L
authors.initials: EL
authors.lastname: Pearce
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Pearce
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000276:immunology*; D019069:Cell Respiration; D005227:Fatty Acids / Q000378:metabolism*; D006374:Helminthiasis, Animal / Q000276:immunology; D006801:Humans; D015847:Interleukin-4 / Q000276:immunology*; D008066:Lipolysis / Q000276:immunology*; D008247:Lysosomes / Q000276:immunology*; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D019948:Receptors, Interleukin-4 / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D002787:Sterol Esterase / Q000276:immunology*; D059467:Transcriptome
chemical_list: D018955:CD36 Antigens; D005227:Fatty Acids; D019948:Receptors, Interleukin-4; D015847:Interleukin-4; D002787:Sterol Esterase; C505054:lysosomal acid lipase, mouse
references.citation: J Biol Chem. 2010 Dec 3;285(49):37976-86
references.pmid: 20852327
references.citation: Cell Metab. 2013 Dec 3;18(6):816-30
references.pmid: 24315368
references.citation: EMBO Mol Med. 2012 Oct;4(10):1072-86
references.pmid: 23027612
references.citation: Prog Lipid Res. 2011 Oct;50(4):331-47
references.pmid: 21601592
references.citation: Nat Rev Immunol. 2003 Jan;3(1):23-35
references.pmid: 12511873
references.citation: J Biol Chem. 2006 Dec 29;281(52):40236-41
references.pmid: 17074755
references.citation: J Membr Biol. 1991 May;121(3):261-8
references.pmid: 1865490
references.citation: Cell Tissue Res. 2013 Dec;354(3):887-9
references.pmid: 23963646
references.citation: J Mol Cell Cardiol. 2013 Feb;55:101-10
references.pmid: 22789525
references.citation: Am J Physiol Regul Integr Comp Physiol. 2011 Oct;301(4):R967-74
references.pmid: 21795638
references.citation: J Lipid Res. 2014 Mar;55(3):385-97
references.pmid: 24347527
references.citation: Hum Mol Genet. 2011 Jan 1;20(1):193-201
references.pmid: 20935172
references.citation: Blood. 2010 Jun 10;115(23):4742-9
references.pmid: 20351312
references.citation: Pharmacotherapy. 2000 Mar;20(3):270-9
references.pmid: 10730683
references.citation: PLoS One. 2013 Sep 17;8(9):e74703
references.pmid: 24069331
references.citation: Cell Metab. 2012 Mar 7;15(3):279-91
references.pmid: 22405066
references.citation: Circ Res. 2010 May 28;106(10):1559-69
references.pmid: 20508200
references.citation: Nat Rev Immunol. 2013 Aug;13(8):607-14
references.pmid: 23827958
references.citation: Blood. 2012 Aug 16;120(7):1422-31
references.pmid: 22786879
references.citation: J Biol Chem. 1995 Nov 17;270(46):27766-72
references.pmid: 7499245
references.citation: Immunity. 2012 Jan 27;36(1):68-78
references.pmid: 22206904
references.citation: J Immunol. 1993 Aug 1;151(3):1235-44
references.pmid: 8393043
references.citation: J Biol Chem. 2012 Apr 6;287(15):11629-41
references.pmid: 22356914
references.citation: Science. 2012 Apr 6;336(6077):86-90
references.pmid: 22442384
references.citation: J Lipid Res. 2000 May;41(5):688-96
references.pmid: 10787429
references.citation: Trends Endocrinol Metab. 2009 Mar;20(2):72-7
references.pmid: 19185504
references.citation: Nat Med. 2006 Aug;12(8):955-60
references.pmid: 16892038
references.citation: Am J Pathol. 2006 Sep;169(3):916-26
references.pmid: 16936266
references.citation: J Vis Exp. 2010 Dec 06;(46):
references.pmid: 21189469
references.citation: Science. 2010 Feb 5;327(5966):656-61
references.pmid: 20133564
references.citation: Science. 2011 Jun 10;332(6035):1284-8
references.pmid: 21566158
references.citation: Cell Metab. 2006 Jul;4(1):13-24
references.pmid: 16814729
references.citation: Nature. 2009 Apr 30;458(7242):1131-5
references.pmid: 19339967
references.citation: Biochem J. 2013 Aug 15;454(1):1-11
references.pmid: 23889252
references.citation: J Immunol. 2010 Jul 1;185(1):605-14
references.pmid: 20498354
references.citation: J Immunol. 2006 Nov 15;177(10):7303-11
references.pmid: 17082649
references.citation: Curr Protoc Immunol. 2003 Aug;Chapter 19:Unit 19.12
references.pmid: 18432905
references.citation: J Biol Chem. 1991 Feb 5;266(4):2021-7
references.pmid: 1899234
references.citation: Immunity. 2018 Aug 21;49(2):375-376
references.pmid: 30134202
references.citation: Mediators Inflamm. 2013;2013:198193
references.pmid: 24062612
references.citation: Annu Rev Pathol. 2011;6:275-97
references.pmid: 21034223
references.citation: J Exp Med. 2013 Oct 21;210(11):2477-91
references.pmid: 24101381
references.citation: J Lipid Res. 2001 Apr;42(4):489-500
references.pmid: 11290820
references.citation: Cell Metab. 2011 Jun 8;13(6):655-67
references.pmid: 21641547
references.citation: Nature. 2013 Jan 17;493(7432):346-55
references.pmid: 23325217
references.citation: J Lipid Res. 1998 Nov;39(11):2125-34
references.pmid: 9799798
references.citation: Cell Metab. 2009 Sep;10(3):219-28
references.pmid: 19723498
references.citation: Blood. 2012 Dec 13;120(25):e93-e104
references.pmid: 23074280
references.citation: Semin Immunopathol. 2012 Nov;34(6):829-46
references.pmid: 23053394
references.citation: Circ Cardiovasc Genet. 2011 Aug 1;4(4):403-12
references.pmid: 21606135
references.citation: Nature. 2013 Apr 25;496(7446):445-55
references.pmid: 23619691
references.citation: BMC Genomics. 2013 Dec 05;14:853
references.pmid: 24314139
references.citation: Curr Opin Immunol. 2010 Jun;22(3):314-20
references.pmid: 20189791