Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 32, Issue 8, Pages 1970-U555Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.112.249508
Keywords
resolution of inflammation; resolvins; neutrophil/endothelial interaction; cell trafficking; receptor; omega-3 fatty acids; docosahexaenoic acid
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Funding
- Arthritis Research UK (Foundation Fellowship) [18445]
- Arthritis Research UK (Career Development Fellowship) [19909]
- Wellcome Trust Programme grant [086867/Z/08/Z]
- National Institutes of Health Research
- National Institutes of Health USA [GM38765, DE019938]
- Versus Arthritis [19909] Funding Source: researchfish
- Wellcome Trust [086867/Z/08/Z] Funding Source: Wellcome Trust
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Objective-Resolvin D1 (RvD1) limits neutrophil recruitment during acute inflammation and is derived from omega-3 docosahexaenoic acid to promote catabasis. The contribution of its specific receptors, the lipoxin A(4)/Annexin-A1 receptor formylpeptide receptor 2 (FPR2/ALX) and the orphan receptor G-protein-coupled receptor 32 (GPR32) are of considerable interest. Methods and Results-RvD1 reduced human polymorphonuclear leukocytes recruitment to endothelial cells under shear conditions as quantified using a flow chamber system. Receptor-specific antibodies blocked these anti-inflammatory actions of RvD1, with low (1 nmol/L) concentrations sensitive to GPR32 blockade, while the higher (10 nmol/L) concentration appeared FPR2/ALX-specific. Interestingly, polymorphonuclear leukocytes surface expression of FPR2/ALX but not GPR32 increased following activation with pro-inflammatory stimuli, corresponding with secretory vesicle mobilization. Lipid mediator metabololipidomics carried out with 24-hour exudates revealed that RvD1 in vivo gave a significant reduction in the levels of a number of pro-inflammatory mediators including prostaglandins and leukotriene B-4. These actions of RvD1 were abolished in fpr2 null mice. Conclusion-Pro-resolving lipid mediators and their receptors, such as RvD1 and the 2 G-protein-coupled receptors, studied here regulate resolution and may provide new therapeutic strategies for diseases with a vascular inflammatory component. (Arterioscler Thromb Vasc Biol. 2012;32:1970-1978.)
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