Cxcl10 is an agonist of the cc family chemokine scavenger receptor ackr2/d6

Andy Chevigné, Bassam Janji, Max Meyrath, Nathan Reynders, Giulia D’uonnolo, Tomasz Uchański, Malina Xiao, Guy Berchem, Markus Ollert, Yong Jun Kwon, Muhammad Zaeem Noman, Martyna Szpakowska*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

Atypical chemokine receptors (ACKRs) are important regulators of chemokine functions. Among them, the atypical chemokine receptor ACKR2 (also known as D6) has long been considered as a scavenger of inflammatory chemokines exclusively from the CC family. In this study, by using highly sensitive β‐arrestin recruitment assays based on NanoBiT and NanoBRET technologies, we identified the inflammatory CXC chemokine CXCL10 as a new strong agonist ligand for ACKR2. CXCL10 is known to play an important role in the infiltration of immune cells into the tumour bed and was previously reported to bind to CXCR3 only. We demonstrated that ACKR2 is able to internalize and reduce the availability of CXCL10 in the extracellular space. Moreover, we found that, in contrast to CC chemokines, CXCL10 activity towards ACKR2 was drastically reduced by the dipep-tidyl peptidase 4 (DPP4 or CD26) N‐terminal processing, pointing to a different receptor binding pocket occupancy by CC and CXC chemokines. Overall, our study sheds new light on the complex-ity of the chemokine network and the potential role of CXCL10 regulation by ACKR2 in many phys-iological and pathological processes, including tumour immunology. Our data also testify that systematic reassessment of chemokine‐receptor pairing is critically needed as important interactions may remain unexplored.

Original languageEnglish
Article number1054
JournalCancers
Volume13
Issue number5
Number of pages13
ISSN2072-6694
DOIs
Publication statusPublished - 1. Mar 2021

Keywords

  • ACKR2
  • ACKR3
  • CD26
  • CXCL10
  • CXCL12
  • CXCL2
  • CXCR3
  • D6
  • DPP4
  • IP‐10
  • NanoBiT
  • NanoBRET
  • Scavenger

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