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Nonredundant role of CCRL2 in lung dendritic cell trafficking.

ABSTRACT: Chemokine CC motif receptor-like 2 (CCRL2) is a heptahelic transmembrane receptor that shows the highest degree of homology with CCR1, an inflammatory chemokine receptor. CCRL2 mRNA was rapidly (30 minutes) and transiently (2-4 hours) 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 T helper cell 2 response. CCRL2(-/-) mice were protected in a model of ovalbumin-induced airway inflammation, with reduced leukocyte recruitment in the BAL (eosinophils and mononuclear cells) and reduced production of the T helper cell 2 cytokines, interleukin-4 and -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 knockout 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.

SUBMITTER: Otero K

PROVIDER: S-EPMC3389732 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Nonredundant role of CCRL2 in lung dendritic cell trafficking.

Otero Karel K Vecchi Annunciata A Hirsch Emilio E Kearley Jennifer J Vermi William W Del Prete Annalisa A Gonzalvo-Feo Safiyè S Garlanda Cecilia C Azzolino Ornella O Salogni Laura L Lloyd Clare M CM Facchetti Fabio F Mantovani Alberto A Sozzani Silvano S

Blood 20100706 16

Chemokine CC motif receptor-like 2 (CCRL2) is a heptahelic transmembrane receptor that shows the highest degree of homology with CCR1, an inflammatory chemokine receptor. CCRL2 mRNA was rapidly (30 minutes) and transiently (2-4 hours) 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 lun ...[more]

PMID: 20606167

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Project description:BACKGROUND: Peripheral blood monocytes (PBMo) originate from the bone marrow, circulate in the blood and emigrate into various organs where they differentiate into tissue resident cellular phenotypes of the mononuclear phagocyte system, including macrophages (Mphi) and dendritic cells (DC). Like in other organs, this emigration and differentiation process is essential to replenish the mononuclear phagocyte pool in the lung under both inflammatory and non-inflammatory steady-state conditions. While many studies have addressed inflammation-driven monocyte trafficking to the lung, the emigration and pulmonary differentiation of PBMo under non-inflammatory conditions is much less understood. METHODS: In order to assess the transcriptional profile of circulating and lung resident mononuclear phagocyte phenotypes, PBMo, lung Mphi and lung DC from naïve mice were flow-sorted to high purity, and their gene expression was compared by DNA microarrays on a genome-wide scale. Differential regulation of selected genes was validated by quantitative PCR and on protein level by flow cytometry. RESULTS: Differentially-expressed genes related to cell traffic were selected and grouped into the clusters (i) matrix metallopeptidases, (ii) chemokines/chemokine receptors, and (iii) integrins. Expression profiles of clustered genes were further assessed at the mRNA and protein levels in subsets of circulating PBMo (GR1- vs GR1+) and lung resident macrophages (alveolar vs interstitial Mphi). Our data identify differentially activated genetic programs in circulating monocytes and their lung descendents. Lung DC activate an extremely diverse set of gene families but largely preserve a mobile cell profile with high expression levels of integrin and chemokine/chemokine receptors. In contrast, interstitial and even more pronounced alveolar Mphi, stepwise downregulate gene expression of these traffic relevant communication molecules, but strongly upregulate a distinct set of matrix metallopetidases potentially involved in tissue invasion and remodeling. CONCLUSION: Our data provide new insight in the changes of the genetic profiles of PBMo and their lung descendents, namely DC and Mphi under non-inflammatory, steady-state conditions. These findings will help to better understand the complex relations within the mononuclear phagocyte pool of the lung.

Dataset Information

Nonredundant role of CCRL2 in lung dendritic cell trafficking.

Publications

Nonredundant role of CCRL2 in lung dendritic cell trafficking.

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