GPR110 (ADGRF1) mediates anti-inflammatory effects of N-docosahexaenoylethanolamine
Abstract Background Neuroinflammation is a widely accepted underlying condition for various pathological processes in the brain. In a recent study, synaptamide, an endogenous metabolite derived from docosahexaenoic acid (DHA, 22:6n-3), was identified as a specific ligand to orphan adhesion G-protein...
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| Format: | Article |
| Language: | English |
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BMC
2019-11-01
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| Series: | Journal of Neuroinflammation |
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| Online Access: | http://link.springer.com/article/10.1186/s12974-019-1621-2 |
| _version_ | 1818348530145689600 |
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| author | Taeyeop Park Huazhen Chen Hee-Yong Kim |
| author_facet | Taeyeop Park Huazhen Chen Hee-Yong Kim |
| author_sort | Taeyeop Park |
| collection | DOAJ |
| description | Abstract Background Neuroinflammation is a widely accepted underlying condition for various pathological processes in the brain. In a recent study, synaptamide, an endogenous metabolite derived from docosahexaenoic acid (DHA, 22:6n-3), was identified as a specific ligand to orphan adhesion G-protein-coupled receptor 110 (GPR110, ADGRF1). Synaptamide has been shown to suppress lipopolysaccharide (LPS)-induced neuroinflammation in mice, but involvement of GPR110 in this process has not been established. In this study, we investigated the possible immune regulatory role of GPR110 in mediating the anti-neuroinflammatory effects of synaptamide under a systemic inflammatory condition. Methods For in vitro studies, we assessed the role of GPR110 in synaptamide effects on LPS-induced inflammatory responses in adult primary mouse microglia, immortalized murine microglial cells (BV2), primary neutrophil, and peritoneal macrophage by using quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA) as well as neutrophil migration and ROS production assays. To evaluate in vivo effects, wild-type (WT) and GPR110 knock-out (KO) mice were injected with LPS intraperitoneally (i.p.) or TNF intravenously (i.v.) followed by synaptamide (i.p.), and expression of proinflammatory mediators was measured by qPCR, ELISA, and western blot analysis. Activated microglia in the brain and NF-kB activation in cells were examined microscopically after immunostaining for Iba-1 and RelA, respectively. Results Intraperitoneal (i.p.) administration of LPS increased TNF and IL-1β in the blood and induced pro-inflammatory cytokine expression in the brain. Subsequent i.p. injection of the GPR110 ligand synaptamide significantly reduced LPS-induced inflammatory responses in wild-type (WT) but not in GPR110 knock-out (KO) mice. In cultured microglia, synaptamide increased cAMP and inhibited LPS-induced proinflammatory cytokine expression by inhibiting the translocation of NF-κB subunit RelA into the nucleus. These effects were abolished by blocking synaptamide binding to GPR110 using an N-terminal targeting antibody. GPR110 expression was found to be high in neutrophils and macrophages where synaptamide also caused a GPR110-dependent increase in cAMP and inhibition of LPS-induced pro-inflammatory mediator expression. Intravenous injection of TNF, a pro-inflammatory cytokine that increases in the circulation after LPS treatment, elicited inflammatory responses in the brain which were dampened by the subsequent injection (i.p.) of synaptamide in a GPR110-dependent manner. Conclusion Our study demonstrates the immune-regulatory function of GPR110 in both brain and periphery, collectively contributing to the anti-neuroinflammatory effects of synaptamide under a systemic inflammatory condition. We suggest GPR110 activation as a novel therapeutic strategy to ameliorate inflammation in the brain as well as periphery. |
| first_indexed | 2024-12-13T17:51:31Z |
| format | Article |
| id | doaj.art-a6d6e2917c2d4b8aa21c505b2ff0aa9c |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-13T17:51:31Z |
| publishDate | 2019-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-a6d6e2917c2d4b8aa21c505b2ff0aa9c2022-12-21T23:36:29ZengBMCJournal of Neuroinflammation1742-20942019-11-0116111310.1186/s12974-019-1621-2GPR110 (ADGRF1) mediates anti-inflammatory effects of N-docosahexaenoylethanolamineTaeyeop Park0Huazhen Chen1Hee-Yong Kim2Laboratory of Molecular Signaling, National Institute of Alcohol Abuse and AlcoholismLaboratory of Molecular Signaling, National Institute of Alcohol Abuse and AlcoholismLaboratory of Molecular Signaling, National Institute of Alcohol Abuse and AlcoholismAbstract Background Neuroinflammation is a widely accepted underlying condition for various pathological processes in the brain. In a recent study, synaptamide, an endogenous metabolite derived from docosahexaenoic acid (DHA, 22:6n-3), was identified as a specific ligand to orphan adhesion G-protein-coupled receptor 110 (GPR110, ADGRF1). Synaptamide has been shown to suppress lipopolysaccharide (LPS)-induced neuroinflammation in mice, but involvement of GPR110 in this process has not been established. In this study, we investigated the possible immune regulatory role of GPR110 in mediating the anti-neuroinflammatory effects of synaptamide under a systemic inflammatory condition. Methods For in vitro studies, we assessed the role of GPR110 in synaptamide effects on LPS-induced inflammatory responses in adult primary mouse microglia, immortalized murine microglial cells (BV2), primary neutrophil, and peritoneal macrophage by using quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA) as well as neutrophil migration and ROS production assays. To evaluate in vivo effects, wild-type (WT) and GPR110 knock-out (KO) mice were injected with LPS intraperitoneally (i.p.) or TNF intravenously (i.v.) followed by synaptamide (i.p.), and expression of proinflammatory mediators was measured by qPCR, ELISA, and western blot analysis. Activated microglia in the brain and NF-kB activation in cells were examined microscopically after immunostaining for Iba-1 and RelA, respectively. Results Intraperitoneal (i.p.) administration of LPS increased TNF and IL-1β in the blood and induced pro-inflammatory cytokine expression in the brain. Subsequent i.p. injection of the GPR110 ligand synaptamide significantly reduced LPS-induced inflammatory responses in wild-type (WT) but not in GPR110 knock-out (KO) mice. In cultured microglia, synaptamide increased cAMP and inhibited LPS-induced proinflammatory cytokine expression by inhibiting the translocation of NF-κB subunit RelA into the nucleus. These effects were abolished by blocking synaptamide binding to GPR110 using an N-terminal targeting antibody. GPR110 expression was found to be high in neutrophils and macrophages where synaptamide also caused a GPR110-dependent increase in cAMP and inhibition of LPS-induced pro-inflammatory mediator expression. Intravenous injection of TNF, a pro-inflammatory cytokine that increases in the circulation after LPS treatment, elicited inflammatory responses in the brain which were dampened by the subsequent injection (i.p.) of synaptamide in a GPR110-dependent manner. Conclusion Our study demonstrates the immune-regulatory function of GPR110 in both brain and periphery, collectively contributing to the anti-neuroinflammatory effects of synaptamide under a systemic inflammatory condition. We suggest GPR110 activation as a novel therapeutic strategy to ameliorate inflammation in the brain as well as periphery.http://link.springer.com/article/10.1186/s12974-019-1621-2GPR110SynaptamidecAMPNeuroinflammationNF-κBDocosahexaenoic acid |
| spellingShingle | Taeyeop Park Huazhen Chen Hee-Yong Kim GPR110 (ADGRF1) mediates anti-inflammatory effects of N-docosahexaenoylethanolamine Journal of Neuroinflammation GPR110 Synaptamide cAMP Neuroinflammation NF-κB Docosahexaenoic acid |
| title | GPR110 (ADGRF1) mediates anti-inflammatory effects of N-docosahexaenoylethanolamine |
| title_full | GPR110 (ADGRF1) mediates anti-inflammatory effects of N-docosahexaenoylethanolamine |
| title_fullStr | GPR110 (ADGRF1) mediates anti-inflammatory effects of N-docosahexaenoylethanolamine |
| title_full_unstemmed | GPR110 (ADGRF1) mediates anti-inflammatory effects of N-docosahexaenoylethanolamine |
| title_short | GPR110 (ADGRF1) mediates anti-inflammatory effects of N-docosahexaenoylethanolamine |
| title_sort | gpr110 adgrf1 mediates anti inflammatory effects of n docosahexaenoylethanolamine |
| topic | GPR110 Synaptamide cAMP Neuroinflammation NF-κB Docosahexaenoic acid |
| url | http://link.springer.com/article/10.1186/s12974-019-1621-2 |
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