Functional Analysis of Free Fatty Acid Receptor GPR120 in Human Eosinophils: Implications in Metabolic Homeostasis

Abstract

Recent evidence has shown that eosinophils play an important role in metabolic homeostasis through Th2 cytokine production. GPR120 (FFA4) is a G protein-coupled receptor (GPCR) for long-chain fatty acids that functions as a regulator of physiological energy metabolism. In the present study, we aimed to investigate whether human eosinophils express GPR120 and, if present, whether it possesses a functional capacity on eosinophils. Eosinophils isolated from peripheral venous blood expressed GPR120 at both the mRNA and protein levels. Stimulation with a synthetic GPR120 agonist, GW9508, induced rapid down-regulation of cell surface expression of GPR120, suggesting ligand-dependent receptor internalization. Although GPR120 activation did not induce eosinophil chemotactic response and degranulation, we found that GW9508 inhibited eosinophil spontaneous apoptosis and Fas receptor expression. The anti-apoptotic effect was attenuated by phosphoinositide 3-kinase (PI3K) inhibitors and was associated with inhibition of caspase-3 activity. Eosinophil response investigated using ELISpot assay indicated that stimulation with a GPR120 agonist induced IL-4 secretion. These findings demonstrate the novel functional properties of fatty acid sensor GPR120 on human eosinophils and indicate the previously unrecognized link between nutrient metabolism and the immune system.

Shaping eosinophil identity in the tissue contexts of development, homeostasis, and disease

“…The stimulation of eosinophils with a synthetic GPR120 agonist led to the increased expression of IL‐4 and the inhibition of apoptosis. These findings suggest that eosinophils might function as nutrient sensors . Finally, there is a strong link between eosinophils and the arachidonic acid metabolism.…”

“…Human eosinophils also express retinoic acid receptors (RARs); retinoic acids are potent inhibitors of human eosinophil apoptosis and upregulate eosinophil expression of CCR3 . Moreover, human eosinophils have been shown to express multiple prostaglandin receptors and GPR120, a G protein‐coupled receptor for long‐chain fatty acids . The stimulation of eosinophils with a synthetic GPR120 agonist led to the increased expression of IL‐4 and the inhibition of apoptosis.…”

“…Eosinophils are emerging as potentially critical regulators of metabolic homeostasis . In murine models, eosinophils present in visceral adipose tissue secrete IL‐4 that causes subcutaneous WAT macrophages to polarize toward the alternatively activated phenotype .…”

“…83 Moreover, human eosinophils have been shown to express multiple prostaglandin receptors 84 and GPR120, a G protein-coupled receptor for long-chain fatty acids. 85 The stimulation of eosinophils with a synthetic GPR120 agonist led to the increased expression of IL-4 and the inhibition of apoptosis. These findings suggest that eosinophils might function as nutrient sensors.…”

Oral administration of the selective GPR120/FFA4 agonist compound A is not effective in alleviating tissue inflammation in mouse models of prototypical autoimmune diseases

“…To date, most extensively investigated physiological role of GPR120/FFA4 is its positive effect on insulin sensitivity, which has sparked broad interest into the development of GPR120/FFA4 agonists as novel antidiabetics . In recent years, it has been shown that FFA4 is also expressed on immune cells, including monocytes/macrophages, dendritic cells, and eosinophils, suggesting that GPR120/FFA4 may mediate immunomodulatory actions of ω3‐PUFAs. In line with this notion, in vitro activation of GPR120/FFA4 in macrophages curbs their immune response to NLPR3 inflammasome, TLR4, or TNF‐α activation, and in vivo GPR120 is required for ω3‐PUFAs to counteract adipose tissue inflammation induced by high‐fat diet in mice by limiting the recruitment of monocyte/macrophages into adipose and reducing the release of proinflammatory M1 macrophage‐derived immunomediators, such as IL‐1β, TNF‐α, MCP‐1, and IL‐6, while in parallel promoting the expression of antiinflammatory M2 macrophages, such as IL‐10, arginase 1, Ym‐1, and Clec7a .…”