Journal
BLOOD
Volume 130, Issue 10, Pages 1223-1234Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2017-04-777680
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Funding
- European Project Innovative Medicines Initiative Joint Undertaking project BeTheCure [115142-2]
- Associazione Italiana Ricerca sul Cancro, Fondazione Berlucchi, Interuniversity Attraction Poles 7-40 program
- Spanish Ministry of Economy and Competitiveness [SAF-2014-53416-R]
- RETICS Program [RD12/0009/009 RIER, RD16/0012/0006]
- COMFUTURO program of the Spanish Ministry of Economy and Competitiveness General foundation
- European Research Council (ERC) Advanced Grant by the European Commission
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CCRL2 is a 7-transmembrane domain receptor that shares structural and functional similarities with the family of atypical chemokine receptors (ACKRs). CCRL2 is upregulated by inflammatory signals and, unlike other ACKRs, it is not a chemoattractant-scavenging receptor, does not activate beta-arrestins, and is widely expressed by many leukocyte subsets. Therefore, the biological role of CCRL2 in immunity is still unclear. We report that CCRL2-deficient mice have a defect in neutrophil recruitment and are protected in 2 models of inflammatory arthritis. In vitro, CCRL2 was found to constitutively form homodimers and heterodimers with CXCR2, a main neutrophil chemotactic receptor. By heterodimerization, CCRL2 could regulate membrane expression and promote CXCR2 functions, including the activation of beta 2-integrins. Therefore, upregulation of CCRL2 observed under inflammatory conditions is functional to finely tune CXCR2-mediated neutrophil recruitment at sites of inflammation.
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