The University of Southampton
University of Southampton Institutional Repository

Omega-3 fatty acids and inflammation: novel interactions reveal a new step in neutrophil recruitment

Omega-3 fatty acids and inflammation: novel interactions reveal a new step in neutrophil recruitment
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-?, 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-D2 (PGD2) 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 PGD3. This alternative series eicosanoid inhibited the migration of neutrophils across endothelial cells by antagonising the PGD2 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. PGD2 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
1-11
Tull, Samantha P.
3aba343f-c097-4e7c-a873-b0526ba36f44
Yates, Clara M.
bf31d73c-79ec-43b9-8c6c-ee12023a8c09
Maskrey, Benjamin H.
10737f92-5822-4d33-97c7-74285bc4d8e3
O'Donnell, Valerie B.
377438e6-bcba-4cdd-9e97-4d1cfd3f5425
Madden, Jackie
0771e352-d432-41ea-8a7e-4704c1efca46
Grimble, Robert F.
3100e4d2-8f29-4ca6-a95d-38a6a764865f
Calder, Philip C.
1797e54f-378e-4dcb-80a4-3e30018f07a6
Nash, Gerard B.
2a1bc801-f2bf-47ba-be93-e259f47fe9c5
Rainger, G. Ed
f437d109-e403-40a4-895a-21f740503a86
Tull, Samantha P.
3aba343f-c097-4e7c-a873-b0526ba36f44
Yates, Clara M.
bf31d73c-79ec-43b9-8c6c-ee12023a8c09
Maskrey, Benjamin H.
10737f92-5822-4d33-97c7-74285bc4d8e3
O'Donnell, Valerie B.
377438e6-bcba-4cdd-9e97-4d1cfd3f5425
Madden, Jackie
0771e352-d432-41ea-8a7e-4704c1efca46
Grimble, Robert F.
3100e4d2-8f29-4ca6-a95d-38a6a764865f
Calder, Philip C.
1797e54f-378e-4dcb-80a4-3e30018f07a6
Nash, Gerard B.
2a1bc801-f2bf-47ba-be93-e259f47fe9c5
Rainger, G. Ed
f437d109-e403-40a4-895a-21f740503a86

Tull, Samantha P., Yates, Clara M., Maskrey, Benjamin H., O'Donnell, Valerie B., Madden, Jackie, Grimble, Robert F., Calder, Philip C., Nash, Gerard B. and Rainger, G. Ed (2009) Omega-3 fatty acids and inflammation: novel interactions reveal a new step in neutrophil recruitment. PLoS Biology, 7 (8), 1-11. (doi:10.1371/journal.pbio.1000177). (PMID:19707265)

Record type: Article

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-?, 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-D2 (PGD2) 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 PGD3. This alternative series eicosanoid inhibited the migration of neutrophils across endothelial cells by antagonising the PGD2 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. PGD2 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

Text
326_Tull_et_al_PLOS_Biol.pdf - Version of Record
Download (437kB)

More information

Submitted date: 6 February 2009
Published date: 25 August 2009
Organisations: Faculty of Medicine, Dev Origins of Health & Disease

Identifiers

Local EPrints ID: 72916
URI: https://eprints.soton.ac.uk/id/eprint/72916
PURE UUID: beb6cedb-2fd5-46d2-b836-4df96c6fbc8c

Catalogue record

Date deposited: 24 Feb 2010
Last modified: 27 Apr 2018 16:31

Export record

Altmetrics

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×