title: M2 Macrophage Polarization Mediates Anti-inflammatory Effects of Endothelial Nitric Oxide Signaling.
abstract: Endothelial nitric oxide (NO) signaling plays a physiological role in limiting obesity-associated insulin resistance and inflammation. This study was undertaken to investigate whether this NO effect involves polarization of macrophages toward an anti-inflammatory M2 phenotype. Mice with transgenic endothelial NO synthase overexpression were protected against high-fat diet (HFD)-induced hepatic inflammation and insulin resistance, and this effect was associated with reduced proinflammatory M1 and increased anti-inflammatory M2 activation of Kupffer cells. In cell culture studies, exposure of macrophages to endothelial NO similarly reduced inflammatory (M1) and increased anti-inflammatory (M2) gene expression. Similar effects were induced by macrophage overexpression of vasodilator-stimulated phosphoprotein (VASP), a key downstream mediator of intracellular NO signaling. Conversely, VASP deficiency induced proinflammatory M1 macrophage activation, and the transplantation of bone marrow from VASP-deficient donor mice into normal recipients caused hepatic inflammation and insulin resistance resembling that induced in normal mice by consumption of an HFD. These data suggest that proinflammatory macrophage M1 activation and macrophage-mediated inflammation are tonically inhibited by NO → VASP signal transduction, and that reduced NO → VASP signaling is involved in the effect of HFD feeding to induce M1 activation of Kupffer cells and associated hepatic inflammation. Our data implicate endothelial NO → VASP signaling as a physiological determinant of macrophage polarization and show that signaling via this pathway is required to prevent hepatic inflammation and insulin resistance.
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA Diabetes and Obesity Center of Excellence, University of Washington, Seattle, WA.
authors.forename: Woo Je
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA Diabetes and Obesity Center of Excellence, University of Washington, Seattle, WA.
authors.forename: Sanshiro
authors.initials: S
authors.lastname: Tateya
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA Diabetes and Obesity Center of Excellence, University of Washington, Seattle, WA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Cheng
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA Diabetes and Obesity Center of Excellence, University of Washington, Seattle, WA.
authors.forename: Norma
authors.initials: N
authors.lastname: Rizzo-DeLeon
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA Diabetes and Obesity Center of Excellence, University of Washington, Seattle, WA.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA Diabetes and Obesity Center of Excellence, University of Washington, Seattle, WA.
authors.forename: Priya
authors.initials: P
authors.lastname: Handa
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA.
authors.forename: Carole L
authors.initials: CL
authors.lastname: Wilson
authors.affiliation: Department of Surgery, University of Washington, Seattle, WA.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Clowes
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA Diabetes and Obesity Center of Excellence, University of Washington, Seattle, WA.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Sweet
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Karol
authors.initials: K
authors.lastname: Bomsztyk
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA Diabetes and Obesity Center of Excellence, University of Washington, Seattle, WA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Schwartz
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA Diabetes and Obesity Center of Excellence, University of Washington, Seattle, WA fkim@u.washington.edu.
authors.forename: Francis
authors.initials: F
authors.lastname: Kim
mesh_terms: D000818:Animals; D016764:Cell Polarity / Q000502:physiology*; D004730:Endothelium, Vascular / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D007728:Kupffer Cells / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008262:Macrophage Activation / Q000502:physiology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014280:Triglycerides / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D014280:Triglycerides; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III
references.citation: J Clin Invest. 2003 Dec;112(12):1796-808
references.pmid: 14679176
references.citation: Arterioscler Thromb Vasc Biol. 2004 Mar;24(3):445-50
references.pmid: 14707037
references.citation: Nitric Oxide. 2004 May;10(3):156-61
references.pmid: 15158695
references.citation: Curr Opin Clin Nutr Metab Care. 2005 Jul;8(4):347-54
references.pmid: 15930956
references.citation: Chem Soc Rev. 2012 May 21;41(10):3742-52
references.pmid: 22362384
references.citation: Am J Physiol Gastrointest Liver Physiol. 2012 Jul;303(1):G103-10
references.pmid: 22517771
references.citation: Science. 2013 Jan 11;339(6116):172-7
references.pmid: 23307735
references.citation: Diabetes. 2013 Jun;62(6):1913-22
references.pmid: 23349495
references.citation: J Biol Chem. 2013 May 31;288(22):16004-15
references.pmid: 23546878
references.citation: J Biol Chem. 2014 Apr 11;289(15):10318-29
references.pmid: 24385430
references.citation: Nat Rev Immunol. 2011 Nov;11(11):738-49
references.pmid: 21984069
references.citation: Oncogene. 2000 May 15;19(21):2577-84
references.pmid: 10851056
references.citation: Diabetes. 2000 May;49(5):684-7
references.pmid: 10905473
references.citation: Biochem J. 2000 Jul 1;349(Pt 1):353-6
references.pmid: 10861247
references.citation: Antioxid Redox Signal. 2000 Fall;2(3):391-6
references.pmid: 11229352
references.citation: Circulation. 2001 Jul 17;104(3):342-5
references.pmid: 11457755
references.citation: Expert Opin Investig Drugs. 2002 May;11(5):587-601
references.pmid: 11996642
references.citation: J Clin Invest. 2003 Sep;112(5):725-35
references.pmid: 12952921
references.citation: Dev Cell. 2003 Nov;5(5):666-8
references.pmid: 14602065
references.citation: J Clin Invest. 2006 Jun;116(6):1494-505
references.pmid: 16691291
references.citation: Cell Metab. 2006 Jul;4(1):13-24
references.pmid: 16814729
references.citation: J Clin Invest. 2006 Jul;116(7):1793-801
references.pmid: 16823477
references.citation: Circ Res. 2006 Jul 7;99(1):78-85
references.pmid: 16763164
references.citation: Am J Physiol Heart Circ Physiol. 2006 Dec;291(6):H2980-6
references.pmid: 16877550
references.citation: Nature. 2006 Dec 14;444(7121):860-7
references.pmid: 17167474
references.citation: J Clin Invest. 2007 Jan;117(1):175-84
references.pmid: 17200717
references.citation: J Biol Chem. 2007 Feb 16;282(7):4601-12
references.pmid: 17082196
references.citation: Diabetes. 2007 Apr;56(4):1025-33
references.pmid: 17229936
references.citation: Circ Res. 2007 Jun 8;100(11):1589-96
references.pmid: 17478729
references.citation: Arterioscler Thromb Vasc Biol. 2004 Aug;24(8):1403-8
references.pmid: 15178555
references.citation: J Clin Invest. 1998 Dec 15;102(12):2061-71
references.pmid: 9854041
references.citation: Arterioscler Thromb Vasc Biol. 2005 May;25(5):989-94
references.pmid: 15731493
references.citation: J Clin Invest. 2005 Jul;115(7):1806-15
references.pmid: 16007254
references.citation: Diabetologia. 2005 Sep;48(9):1933-40
references.pmid: 16034613
references.citation: Nat Rev Immunol. 2005 Dec;5(12):953-64
references.pmid: 16322748
references.citation: Eur Urol. 2008 Jun;53(6):1272-80
references.pmid: 18036727
references.citation: Cell Metab. 2008 Jun;7(6):496-507
references.pmid: 18522831
references.citation: Cell Metab. 2008 Oct;8(4):301-9
references.pmid: 18840360
references.citation: Arterioscler Thromb Vasc Biol. 2008 Nov;28(11):1982-8
references.pmid: 18772497
references.citation: Nat Clin Pract Endocrinol Metab. 2008 Nov;4(11):619-26
references.pmid: 18838972
references.citation: Trends Endocrinol Metab. 2009 Aug;20(6):295-302
references.pmid: 19647446
references.citation: Nat Rev Immunol. 2009 Oct;9(10):692-703
references.pmid: 19859064
references.citation: Annu Rev Physiol. 2010;72:219-46
references.pmid: 20148674
references.citation: Arterioscler Thromb Vasc Biol. 2010 Apr;30(4):758-65
references.pmid: 20093624
references.citation: Cell. 2010 Mar 19;140(6):805-20
references.pmid: 20303872
references.citation: Diabetes. 2010 Apr;59(4):916-25
references.pmid: 20103702
references.citation: J Immunol. 2010 Jul 1;185(1):605-14
references.pmid: 20498354
references.citation: Nat Immunol. 2010 Oct;11(10):889-96
references.pmid: 20856220
references.citation: Proc Natl Acad Sci U S A. 2010 Oct 12;107(41):17716-20
references.pmid: 20876122
references.citation: Immunity. 2010 Nov 24;33(5):699-712
references.pmid: 21093321
references.citation: Proc Natl Acad Sci U S A. 2010 Dec 28;107(52):22617-22
references.pmid: 21149710
references.citation: Annu Rev Pathol. 2011;6:275-97
references.pmid: 21034223
references.citation: Basic Res Cardiol. 2011 Mar;106(2):205-15
references.pmid: 21116821
references.citation: Science. 2011 Jun 10;332(6035):1284-8
references.pmid: 21566158
references.citation: J Clin Invest. 2011 Jul;121(7):2736-49
references.pmid: 21670502
references.citation: Diabetes. 2011 Nov;60(11):2792-801
references.pmid: 21911751
references.citation: Nat Rev Immunol. 2011 Nov;11(11):723-37
references.pmid: 21997792
references.citation: Arterioscler Thromb Vasc Biol. 2011 Dec;31(12):2827-35
references.pmid: 21903940
references.citation: J Clin Invest. 2011 Dec;121(12):4903-15
references.pmid: 22080866
references.citation: J Clin Invest. 2012 Mar;122(3):787-95
references.pmid: 22378047
references.citation: Nature. 2007 Jun 28;447(7148):1116-20
references.pmid: 17515919
references.citation: Cell Metab. 2007 Aug;6(2):96-8
references.pmid: 17681144
references.citation: Cell. 2007 Sep 21;130(6):1083-94
references.pmid: 17825402
references.citation: Am J Physiol Endocrinol Metab. 2008 Jan;294(1):E15-26
references.pmid: 17957034
references.citation: J Cell Biol. 2008 Apr 7;181(1):19-25
references.pmid: 18378777