The atypical receptor CCRL2 is required for CXCR2-dependent neutrophil recruitment and tissue damage

CCRL2 is a seven transmembrane domain receptor that shares structural and functional similarities with the family of the Atypical Chemokine Receptors (ACKRs). CCRL2 is upregulated by inflammatory signals and, unlike from other ACKRs, is not a chemoattractant scavenging receptor, does not activate β-arrestins and is widely expressed by many leukocyte subsets. Therefore, the biological role of CCRL2 in immunity is still unclear. Here we report that CCRL2-deficient mice have a defect in neutrophil recruitment and are protected in two models of inflammatory arthritis. In vitro, CCRL2 was found to constitutively form homo and heterodimers with CXCR2, a main neutrophil chemotactic receptor. By heterodimerization, CCRL2 could regulate membrane expression and promote CXCR2 functions including the activation of β2-integrins. Therefore, upregulation of CCRL2 observed under inflammatory conditions is functional to finely tune CXCR2-mediated neutrophil recruitment at sites of inflammation.