title: Omega-3 Fatty acids and inflammation: novel interactions reveal a new step in neutrophil recruitment.
abstract: Inflammation is a physiological response to tissue trauma or infection, but leukocytes, which are the effector cells of the inflammatory process, have powerful tissue remodelling capabilities. Thus, to ensure their precise localisation, passage of leukocytes from the blood into inflamed tissue is tightly regulated. Recruitment of blood borne neutrophils to the tissue stroma occurs during early inflammation. In this process, peptide agonists of the chemokine family are assumed to provide a chemotactic stimulus capable of supporting the migration of neutrophils across vascular endothelial cells, through the basement membrane of the vessel wall, and out into the tissue stroma. Here, we show that, although an initial chemokine stimulus is essential for the recruitment of flowing neutrophils by endothelial cells stimulated with the inflammatory cytokine tumour necrosis factor-alpha, transit of the endothelial monolayer is regulated by an additional and downstream stimulus. This signal is supplied by the metabolism of the omega-6-polyunsaturated fatty acid (n-6-PUFA), arachidonic acid, into the eicosanoid prostaglandin-D(2) (PGD(2)) by cyclooxygenase (COX) enzymes. This new step in the neutrophil recruitment process was revealed when the dietary n-3-PUFA, eicosapentaenoic acid (EPA), was utilised as an alternative substrate for COX enzymes, leading to the generation of PGD(3). This alternative series eicosanoid inhibited the migration of neutrophils across endothelial cells by antagonising the PGD(2) receptor. Here, we describe a new step in the neutrophil recruitment process that relies upon a lipid-mediated signal to regulate the migration of neutrophils across endothelial cells. PGD(2) signalling is subordinate to the chemokine-mediated activation of neutrophils, but without the sequential delivery of this signal, neutrophils fail to penetrate the endothelial cell monolayer. Importantly, the ability of the dietary n-3-PUFA, EPA, to inhibit this process not only revealed an unsuspected level of regulation in the migration of inflammatory leukocytes, it also contributes to our understanding of the interactions of this bioactive lipid with the inflammatory system. Moreover, it indicates the potential for novel therapeutics that target the inflammatory system with greater affinity and/or specificity than supplementing the diet with n-3-PUFAs.
authors.affiliation: Centre for Cardiovascular Sciences, School of Clinical and Experimental Medicine, The Medical School, The University of Birmingham, Birmingham, United Kingdom.
authors.forename: Samantha P
authors.initials: SP
authors.lastname: Tull
authors.forename: Clara M
authors.initials: CM
authors.lastname: Yates
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Maskrey
authors.forename: Valerie B
authors.initials: VB
authors.lastname: O'Donnell
authors.forename: Jackie
authors.initials: J
authors.lastname: Madden
authors.forename: Robert F
authors.initials: RF
authors.lastname: Grimble
authors.forename: Philip C
authors.initials: PC
authors.lastname: Calder
authors.forename: Gerard B
authors.initials: GB
authors.lastname: Nash
authors.forename: G Ed
authors.initials: GE
authors.lastname: Rainger
mesh_terms: D002448:Cell Adhesion; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics; D054360:Chemokine CXCL1 / Q000235:genetics; D054426:Chemokine CXCL2 / Q000235:genetics; D002853:Chromatography, Liquid; D016861:Cyclooxygenase Inhibitors; D019040:E-Selectin / Q000378:metabolism; D015118:Eicosapentaenoic Acid / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D020556:Neutrophil Infiltration / Q000502:physiology*; D009578:Nitrobenzenes / Q000378:metabolism; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011720:Pyrazoles / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; C499706:CXCL2 protein, human; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D016861:Cyclooxygenase Inhibitors; D019040:E-Selectin; D015525:Fatty Acids, Omega-3; D009578:Nitrobenzenes; D010743:Phospholipids; D011720:Pyrazoles; C115461:SC 560; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D018799:Intercellular Adhesion Molecule-1; D015118:Eicosapentaenoic Acid; D011451:Prostaglandin-Endoperoxide Synthases
references.citation: Thromb Res. 1996 Jan 15;81(2):213-18
references.pmid: 8822136
references.citation: Br J Pharmacol. 1996 Apr;117(8):1792-6
references.pmid: 8732293
references.citation: Annu Rev Physiol. 1995;57:827-72
references.pmid: 7778885
references.citation: J Med Invest. 2007 Aug;54(3-4):243-7
references.pmid: 17878672
references.citation: Cell. 1991 May 31;65(5):859-73
references.pmid: 1710173
references.citation: Microvasc Res. 2005 May;69(3):107-27
references.pmid: 15896353
references.citation: J Cell Sci. 1979 Aug;38:225-35
references.pmid: 230196
references.citation: Blood. 2002 Aug 15;100(4):1354-61
references.pmid: 12149218
references.citation: Arterioscler Thromb Vasc Biol. 1995 May;15(5):622-8
references.pmid: 7538427
references.citation: J Biol Chem. 2004 Aug 6;279(32):33684-95
references.pmid: 15140897
references.citation: Eur J Nutr. 2007 Sep;46(6):321-8
references.pmid: 17712587
references.citation: J Immunol. 2000 Jun 1;164(11):5961-9
references.pmid: 10820279
references.citation: Curr Opin Cell Biol. 1996 Oct;8(5):714-23
references.pmid: 8939652
references.citation: J Immunol. 2002 Jan 1;168(1):443-9
references.pmid: 11751991
references.citation: Kidney Int. 1981 Jun;19(6):755-9
references.pmid: 7021952
references.citation: J Immunol. 2008 Feb 1;180(3):1843-53
references.pmid: 18209082
references.citation: Biochem Pharmacol. 2007 Jun 30;74(1):107-17
references.pmid: 17452035
references.citation: Blood. 2002 Aug 15;100(4):1362-72
references.pmid: 12149219
references.citation: Cardiovasc Res. 1995 May;29(5):670-5
references.pmid: 7606756
references.citation: Clin Chem. 2001 Apr;47(4):768-70
references.pmid: 11274037
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20979-84
references.pmid: 18077391
references.citation: J Immunol. 2004 Jan 1;172(1):7-13
references.pmid: 14688302
references.citation: J Immunol. 2007 Oct 1;179(7):4792-9
references.pmid: 17878378
references.citation: Biochem Biophys Res Commun. 1996 Mar 27;220(3):969-74
references.pmid: 8607877
references.citation: Blood. 1996 Nov 1;88(9):3259-87
references.pmid: 8896391
references.citation: Microvasc Res. 1993 Jan;45(1):33-45
references.pmid: 8479340
references.citation: J Immunol. 2003 Oct 15;171(8):3936-40
references.pmid: 14530310
references.citation: Am J Physiol. 1997 Jan;272(1 Pt 2):H114-22
references.pmid: 9038929
references.citation: J Clin Epidemiol. 1995 Nov;48(11):1379-90
references.pmid: 7490601
references.citation: J Exp Med. 2001 May 21;193(10):1135-47
references.pmid: 11369785
references.citation: Cell Adhes Commun. 1998;6(6):491-501
references.pmid: 9929742
references.citation: Blood. 2004 Mar 1;103(5):1595-601
references.pmid: 14592837
references.citation: Br J Pharmacol. 1985 Jun;85(2):367-75
references.pmid: 2992661
references.citation: Circulation. 2004 Jun 8;109(22):2705-11
references.pmid: 15184295
references.citation: J Cell Sci. 1979 Aug;38:237-48
references.pmid: 391812
references.citation: J Immunol. 2006 Jan 15;176(2):966-73
references.pmid: 16393982
references.citation: Lancet. 2003 Feb 8;361(9356):477-85
references.pmid: 12583947
references.citation: J Leukoc Biol. 2007 Feb;81(2):372-82
references.pmid: 17043246
references.citation: J Exp Med. 2001 Jan 15;193(2):255-61
references.pmid: 11208866