GPR101 mediates the pro-resolving actions of RvD5n-3 DPA in arthritis and infections
| Autor: | Jesmond Dalli, Magdalena B. Flak, James M. Smith, Francesco Palmas, Agua Sobrino, Duco S. Koenis, Kimberly Pistorius |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Neutrophils Inflammatory arthritis Arthritis Macrophages/immunology Receptors G-Protein-Coupled chemistry.chemical_compound Mice 0302 clinical medicine Receptors G-Protein-Coupled/agonists Bacterial infections Arthritis/drug therapy Receptor Docosahexaenoic Acids/pharmacology Escherichia coli Infections Escherichia coli Infections/drug therapy Infectious disease General Medicine 3. Good health Cell biology G-protein coupled receptors 030220 oncology & carcinogenesis Gene Knockdown Techniques medicine.symptom Resolvin Research Article Docosahexaenoic Acids Phagocytosis/drug effects Phagocytosis Inflammation CHO Cells 03 medical and health sciences Cricetulus medicine Escherichia coli Animals Humans Cyclic adenosine monophosphate Efferocytosis Escherichia coli/immunology Macrophages Neutrophils/immunology fungi medicine.disease 030104 developmental biology chemistry |
| Zdroj: | The Journal of Clinical Investigation Flak, M B, Koenis, D S, Sobrino, A, Smith, J, Pistorius, K, Palmas, F & Dalli, J 2020, ' GPR101 mediates the pro-resolving actions of RvD5n-3 DPA in arthritis and infections ', The Journal of clinical investigation, vol. 130, no. 1, pp. 359-373 . https://doi.org/10.1172/JCI131609 Journal of Clinical Investigation |
| ISSN: | 1558-8238 |
| DOI: | 10.1172/JCI131609 |
| Popis: | N-3 docosapentaenoic acid-derived resolvin D5 (RvD5n-3 DPA) is diurnally regulated in peripheral blood and exerts tissue-protective actions during inflammatory arthritis. Here, using an orphan GPCR screening approach coupled with functional readouts, we investigated the receptor(s) involved in mediating the leukocyte-directed actions of RvD5n-3 DPA and identified GPR101 as the top candidate. RvD5n-3 DPA bound to GPR101 with high selectivity and stereospecificity, as demonstrated by a calculated KD of approximately 6.9 nM. In macrophages, GPR101 knockdown limited the ability of RvD5n-3 DPA to upregulate cyclic adenosine monophosphate, phagocytosis of bacteria, and efferocytosis. Inhibition of this receptor in mouse and human leukocytes abrogated the pro-resolving actions of RvD5n-3 DPA, including the regulation of bacterial phagocytosis in neutrophils. Knockdown of the receptor in vivo reversed the protective actions of RvD5n-3 DPA in limiting joint and gut inflammation during inflammatory arthritis. Administration of RvD5n-3 DPA during E. coli-initiated inflammation regulated neutrophil trafficking to the site of inflammation, increased bacterial phagocytosis by neutrophils and macrophages, and accelerated the resolution of infectious inflammation. These in vivo protective actions of RvD5n-3 DPA were limited when Gpr101 was knocked down. Together, our findings demonstrate a fundamental role for GPR101 in mediating the leukocyte-directed actions of RvD5n-3 DPA. |
| Databáze: | OpenAIRE |
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