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The GPR120 Agonist TUG-891 Inhibits the Motility and Phagocytosis of Mouse Alveolar Macrophages.

ABSTRACT: Movement and phagocytosis characterize the fundamental actions of macrophages. Although it is known that the free fatty acid receptor GPR120 is expressed in macrophages and regulates cytokine expression to exert anti-inflammatory activities, the effects of GPR120 activation on the motility and phagocytosis of macrophages are not clear. In this study, mouse alveolar macrophages (AM) were stimulated with the GPR120 agonist TUG-891, and the changes in cell motility, intracellular Ca2+ concentration ([Ca2+]i), and the ability of phagocytosis were measured. Mouse AM in controls exhibited active movement in vitro, and TUG-891 significantly restrained AM movement. Meanwhile, TUG-891 stimulated a quick increase in [Ca2+]i in AM, which was blocked separately by the Gq protein inhibitor YM-254890, the phospholipase C (PLC) inhibitor U73122, or depletion of endoplasmic reticulum (ER) Ca2+ store by thapsigargin. The inhibition of AM movement by TUG-891 was eliminated by YM-254890, U73122, thapsigargin, and chelation of cytosolic Ca2+ by BAPTA. Moreover, TUG-891 inhibited AM phagocytosis of fluorescent microspheres, which was also blocked by YM-254890, U73122, thapsigargin, and BAPTA. In conclusion, GPR120 activation in mouse AM increases [Ca2+]i but inhibits the motility and phagocytosis via Gq protein/PLC-mediated Ca2+ release from ER Ca2+ store.

SUBMITTER: Su XL

PROVIDER: S-EPMC7056993 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The GPR120 Agonist TUG-891 Inhibits the Motility and Phagocytosis of Mouse Alveolar Macrophages.

Su Xing-Li XL Liu Ying-Guang YG Shi Man M Zhao Yan-Yan YY Liang Xiang-Yan XY Zhang Li-Jun LJ Wei Lan-Lan LL Zhao Yu-Feng YF

BioMed research international 20200220

Movement and phagocytosis characterize the fundamental actions of macrophages. Although it is known that the free fatty acid receptor GPR120 is expressed in macrophages and regulates cytokine expression to exert anti-inflammatory activities, the effects of GPR120 activation on the motility and phagocytosis of macrophages are not clear. In this study, mouse alveolar macrophages (AM) were stimulated with the GPR120 agonist TUG-891, and the changes in cell motility, intracellular Ca<sup>2+</sup> co ...[more]

PMID: 32149083

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Project description:BackgroundChronic alcohol consumption impairs alveolar macrophage's (AM) function and increases risk for developing lung infection and pneumonia. However, the mechanism and metabolic basis of alcohol-induced AM dysfunction leading to lung infection are not well defined, but may include altered ethanol (EtOH) and reactive oxygen species metabolism and cellular energetics. Therefore, oxidative stress, endoplasmic reticulum (ER) stress, the formation of fatty acid ethyl esters [FAEEs, nonoxidative metabolites of EtOH], AMP-activated protein kinase (AMPK) signaling, and phagocytic function were examined in freshly isolated AM incubated with EtOH.MethodsAMs separated from bronchoalveolar lavage fluid samples obtained from normal volunteers were incubated with EtOH for 24 hours. AMPK signaling and ER stress were assessed using Western blotting, FAEEs by GC-MS, oxidative stress by immunofluorescence using antibodies to 4-hydroxynonenal, and phagocytosis by latex beads. Oxidative stress was also measured in EtOH-treated AMs with/without AMPK activator [5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)] or inhibitor (Compound C), and in AMs incubated with FAEEs. mRNA expression for interleukins (IL-6 and IL-8), monocyte chemoattractant protein (MCP)-1, and transforming growth factor (TGF)-β was measured in AM treated with EtOH or FAEEs using RT-PCR.ResultsEtOH exposure to AM increased oxidative stress, ER stress, and synthesis of FAEEs, decreased phosphorylated AMPK, and impaired phagocytosis. Attenuation or exacerbation of EtOH-induced oxidative stress by AICAR or Compound C, respectively, suggests a link between AMPK signaling, EtOH metabolism, and related oxidative stress. The formation of FAEEs may contribute to EtOH-induced oxidative stress as FAEEs also produced concentration-dependent oxidative stress. An increased mRNA expression of IL-6, IL-8, and MCP-1 by FAEEs is key finding to suggest a metabolic basis of EtOH-induced inflammatory response.ConclusionsEtOH-induced impaired phagocytosis, oxidative stress, ER stress, and dysregulated AMPK signaling are plausibly associated with the formation of FAEEs and may participate in the pathogenesis of nonspecific pulmonary inflammation.

Dataset Information

The GPR120 Agonist TUG-891 Inhibits the Motility and Phagocytosis of Mouse Alveolar Macrophages.

Publications

The GPR120 Agonist TUG-891 Inhibits the Motility and Phagocytosis of Mouse Alveolar Macrophages.

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