CCRL2, A PUTATIVE CHEMOTACTIC RECEPTOR, PARTICIPATES IN THE LUNG DENDRITIC CELL TRAFFICKING

CCRL2 (chemokine CC motif receptor-like 2) is an orphan heptahelic serpentine receptor that is rapidly induced in dendritic cells (DC) during maturation. CCRL2 shares the highest homology with the inflammatory chemokine receptors CCR1 and CCR5 and the ligand, chemerin, with the chemotactic receptor ChemR23. Although both CCRL2 and ChemR23 are expressed by DC, they show an opposite regulation during DC maturation. In addition, CCRL2 is apparently unable to signal in response to chemerin and was shown to function as a presenting protein of chemerin to ChemR23-expressing cells. In order to evaluate the biological relevance of this receptor, we used CCRL2 deficient mice in an established model of allergen-induced airway inflammation in which DC are known to play a crucial role. CCRL2-/- mice were protected in a model of OVA-induced airway inflammation with reduced leukocyte recruitment in the BAL (eosinophils and mononuclear cells) and reduced production of the Th2 cytokines IL-4 and IL-5 and chemokines CCL11 and CCL17. CCRL2-/- mice showed normal recruitment of circulating DC into the lung but a defective trafficking of antigen-loaded lung DC to mediastinal lymph nodes. This defect was associated to a reduction in lymph node cellularity and reduced priming of Th2 response. Chemerin was expressed by mouse lung vascular endothelial cells and by lymphatic endothelial cells and was found to be upregulated by retinoic acid. Retinoic acid stimulated endothelial cells (EC) promoted the transmigration of DC in a ChemR23-dependent manner, suggesting a role for membrane associated chemerin. The results here reported define chemerin as a new relevant protein for DC trafficking across lymphatic and blood endothelial barriers. In addition, these results highlight a nonredundant role for CCRL2 in the migration of lung DC and in the induction of Th2-polarized airway allergic inflammation. Altogether, this study proposes the CCRL2/chemerin axis as a new potential target for therapeutic strategies aimed at controlling lung hypersensitivity.