Omega-3 Fatty acids and inflammation: novel interactions reveal a new step in neutrophil recruitment.
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.
Tull
Samantha P
SP
Centre for Cardiovascular Sciences, School of Clinical and Experimental Medicine, The Medical School, The University of Birmingham, Birmingham, United Kingdom.
Yates
Clara M
CM
Maskrey
Benjamin H
BH
O'Donnell
Valerie B
VB
Madden
Jackie
J
Grimble
Robert F
RF
Calder
Philip C
PC
Nash
Gerard B
GB
Rainger
G Ed
GE
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
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
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