Evidence for the Existence of a CXCL17 Receptor Distinct from GPR35

Nurul A S Binti Mohd Amir1,2, Amanda E Mackenzie3, Laura Jenkins3

  • 1Inflammation, Repair and Development Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW7 2AZ, United Kingdom.

Insights

This study investigated the chemokine CXCL17 and its potential receptor GPR35. Findings indicate GPR35 is not a receptor for CXCL17, suggesting an unidentified receptor mediates CXCL17

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Chemokine CXCL17 is linked to innate immunity in mucosal tissues but remains poorly understood.
  • G protein-coupled receptor GPR35, found on monocytes and mast cells, is implicated in immune responses, but its exact function is unclear.
  • A prior study suggested GPR35 signals in response to CXCL17, necessitating further investigation.

Purpose of the Study:

  • To confirm or refute the reported interaction between chemokine CXCL17 and GPR35.
  • To investigate the migratory response of human monocytes and THP-1 cells to CXCL17.
  • To identify the receptor responsible for mediating cellular responses to CXCL17.

Main Methods:

  • Assays for beta-arrestin recruitment, inositol phosphate production, calcium flux, and receptor endocytosis to test GPR35 signaling.
  • Chemotaxis assays using varying CXCL17 concentrations with GPR35-expressing cells.
  • Real-time chemotaxis assay (TAXIScan) on human monocytes and THP-1 cells exposed to CXCL17 gradients, with and without PGE2 and GPR35 antagonist ML145.

Main Results:

  • GPR35 failed to signal in response to CXCL17 across multiple functional assays, including beta-arrestin recruitment and calcium flux.
  • Human monocytes showed no migration towards CXCL17, while THP-1 cells exhibited a trend towards migration, enhanced by PGE2.
  • The GPR35 antagonist ML145 did not significantly inhibit the migration of PGE2-treated THP-1 cells towards CXCL17, and CXCL17 cleavage by chymase had minimal impact on recruitment.

Conclusions:

  • GPR35 is unlikely to be a functional receptor for the chemokine CXCL17.
  • THP-1 cells possess an as-yet unidentified receptor that mediates migration in response to CXCL17.
  • Further research is needed to identify the specific receptor for CXCL17 involved in immune cell migration.

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