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Non-redundant role of CCRL2 in lung dendritic cell trafficking

Karel Otero, Annunciata Vecchi, Emilio Hirsch, Jennifer Kearley, William Vermi, Annalisa Del Prete, Safiyè Gonzalvo-Feo, Cecilia Garlanda, Ornella Azzolino, Laura Salogni, Clare M. Lloyd, Fabio Facchetti, Alberto Mantovani and Silvano Sozzani

Abstract

CCRL2 is a heptahelic transmembrane receptor that shows the highest degree of homology with CCR1, an inflammatory chemokine receptor. CCRL2 mRNA was rapidly (30 min) and transiently (2-4 hrs) regulated during dendritic cell (DC) maturation. Protein expression paralleled RNA regulation. In vivo, CCRL2 was expressed by activated DC and macrophages, but not by eosinophils and T cells. 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. 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. The central role of CCRL2 deficiency in DC was supported by the fact that adoptive transfer of CCRL2-/- antigen-loaded DC in wild type animals recapitulated the phenotype observed in knock out mice. These data show a nonredundant role of CCRL2 in lung DC trafficking and propose a role for this receptor in the control of excessive airway inflammatory responses.

  • Submitted December 23, 2009.
  • Accepted June 17, 2010.