GPR101 mediates the pro-resolving actions of RvD5n-3 DPA in arthritis and infections

Magdalena B Flak, Duco S Koenis, Agua Sobrino, James Smith, Kimberly Pistorius, Francesco Palmas, Jesmond Dalli

Research output: Contribution to journalArticlepeer-review

66 Citations (Scopus)
82 Downloads (Pure)

Abstract

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.

Original languageEnglish
Pages (from-to)359-373
Number of pages15
JournalThe Journal of clinical investigation
Volume130
Issue number1
Early online date3 Dec 2019
DOIs
Publication statusPublished - 2 Jan 2020

Keywords

  • Animals
  • Arthritis/drug therapy
  • CHO Cells
  • Cricetulus
  • Docosahexaenoic Acids/pharmacology
  • Escherichia coli/immunology
  • Escherichia coli Infections/drug therapy
  • Gene Knockdown Techniques
  • Humans
  • Macrophages/immunology
  • Male
  • Mice
  • Neutrophils/immunology
  • Phagocytosis/drug effects
  • Receptors, G-Protein-Coupled/agonists

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