Abstract
G-protein-coupled receptor 40 (GPR40) is known to play a role in the regulation of fatty acids, insulin secretion, and inflammation. However, the function of this receptor in human neutrophils, one of the first leukocytes to arrive at the site of infection, remains to be fully elucidated. In the present study, we demonstrate that GPR40 is upregulated on activated human neutrophils and investigated the functional effects upon treatment with a selective agonist; GW9508. Interestingly, GPR40 expression was up-regulated after neutrophil stimulation with platelet-activating factor (10 nM) or leukotriene B4 (LTB4, 10 nM) suggesting potential regulatory roles for this receptor during inflammation. Indeed, GW9508 (1 and 10 μM) increased neutrophil chemotaxis in response to the chemokine IL-8 (30 ng/ml) and enhanced phagocytosis of Escherichia coli by approximately 50% when tested at 0.1 and 1 μM. These results were translated in vivo whereby administration of GW9508 (10 mg/kg, i.p.) during E. coli infections resulted in elevated peritoneal leukocyte infiltration with a higher phagocytic capacity. Importantly, GW9508 administration also modulated the lipid mediator profile, with increased levels of the pro-resolving mediators resolvin D3 and lipoxins. In conclusion, GPR40 is expressed by activated neutrophils and plays an important host protective role to aid clearance of bacterial infections.
Highlights
G-protein-coupled receptor 40 (GPR40; known as free fatty acid receptor 1, FFAR1), is a member of the G-protein coupled receptor (GPCR) family
GPR40 expression was significantly higher on exudate neutrophils when compared ethanol), TNF-α (10 ng/ml), IL-8 (10 ng/ml), platelet-activating factor (PAF) (10 nM) or leukotriene B4 (LTB4) (10 nM) for 10 min at 37◦C, and GPR40 expression monitored by flow cytometry
Results are mean ± SEM, n = 4 *p < 0.05 and **p < 0.01 vs. vehicle control using one-way ANOVA, followed by Dunnett’s post-test. (B) Representative images of GPR40 expression in unstimulated neutrophils (CD11blowCD62Lhi) by ImagestreamTX (60x). (C–E) Neutrophils were isolated from the peripheral blood and from the buccal cavity after mouth wash with TabascoTM from healthy individuals and expression of (C) CD11b, (D) L-selectin, and (E) GPR40 was monitored by flow cytometry, representative histograms are shown inset
Summary
G-protein-coupled receptor 40 (GPR40; known as free fatty acid receptor 1, FFAR1), is a member of the G-protein coupled receptor (GPCR) family. Many agonists have been discovered to bind and activate GPR40 such as medium- and long-chain fatty acids, including omega-3 docosahexaenoic acid (DHA) [1] as well as 17,18-epoxyeicosatetraenoic acid (17,18-EpETE), a bioactive lipid mediator (LM) derived from eicosapentaenoic acid (EPA) [2]. Due to its pivotal role in insulin regulation a number of synthetic agonists have been developed such as Fasiglifam (TAK-875) and GW9508, which exert beneficial. There is evidence that GPR40 plays a role in regulating the inflammatory response, for example by counteracting inflammasome activation and limiting contact hypersensitivity [6, 2]. The functional role of GPR40 in the context of the innate immune response to infection and whether it plays a role in the resolution of inflammation remains to be fully elucidated
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