| Zdroj: |
Fredriksson, J, Holdfeldt, A, Mårtensson, J, Björkman, L, Møller, T C, Müllers, E, Dahlgren, C, Sundqvist, M & Forsman, H 2022, ' GRK2 selectively attenuates the neutrophil NADPH-oxidase response triggered by β-arrestin recruiting GPR84 agonists ', Biochimica et Biophysica Acta-Molecular Cell Research, vol. 1869, no. 7, 119262 . https://doi.org/10.1016/j.bbamcr.2022.119262 |
| Popis: |
In order to avoid a prolonged pro-inflammatory neutrophil response, signaling downstream of an agonist-activated G protein-coupled receptor (GPCR) has to be rapidly terminated. Among the family of GPCR kinases (GRKs) that regulate receptor phosphorylation and signaling termination, GRK2, which is highly expressed by immune cells, plays an important role. The medium chain fatty acid receptor GPR84 as well as formyl peptide receptor 2 (FPR2), receptors expressed in neutrophils, play a key role in regulating inflammation. In this study, we investigated the effects of GRK2 inhibitors on neutrophil functions induced by GPR84 and FPR2 agonists. GRK2 was shown to be expressed in human neutrophils and analysis of subcellular fractions revealed a cytosolic localization. The GRK2 inhibitors enhanced and prolonged neutrophil production of reactive oxygen species (ROS) induced by GPR84- but not FPR2-agonists, suggesting a receptor selective function of GRK2. This suggestion was supported by β-arrestin recruitment data. The ROS production induced by a non β-arrestin recruiting GPR84 agonist was not affected by the GRK2 inhibitor. Termination of this β-arrestin independent response relied, similar to the response induced by FPR2 agonists, primarily on the actin cytoskeleton. In summary, we show that GPR84 utilizes GRK2 in concert with β-arrestin and actin cytoskeleton dependent processes to fine-tune the activity of the ROS generating NADPH-oxidase in neutrophils. |
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