Signal relay by CC chemokine receptor 2 (CCR2) and formylpeptide receptor 2 (Fpr2) in the recruitment of monocyte-derived dendritic cells in allergic airway inflammation.

J Biol Chem. 2013 Jun 7;288(23):16262-73.


Chen K, Liu M, Liu Y, Wang C, Yoshimura T, Gong W, Le Y, Tessarollo L, Wang JM

Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research and National Cancer Institutes, Frederick, Maryland21702



Chemoattractant receptors regulate leukocyte accumulation at sites of inflammation. In allergic airway inflammation, although a chemokine receptor CCR2 was implicated in mediating monocyte-derived dendritic cell (DC) recruitment into the lung, we previously also discovered reduced accumulation of DCs in the inflamed lung in mice deficient in formylpeptide receptor Fpr2 (Fpr2(-/-)). We therefore investigated the role of Fpr2 in the trafficking of monocyte-derived DCs in allergic airway inflammation in cooperation with CCR2. We report that in allergic airway inflammation, CCR2 mediated the recruitment of monocyte-derived DCs to the perivascular region, and Fpr2 was required for further migration of the cells into the bronchiolar area. We additionally found that the bronchoalveolar lavage liquid from mice with airway inflammation contained both the CCR2 ligand CCL2 and an Fpr2 agonist CRAMP. Furthermore, similar to Fpr2(-/-) mice, in the inflamed airway of CRAMP(-/-) mice, DC trafficking into the peribronchiolar areas was diminished. Our study demonstrates that the interaction of CCR2 and Fpr2 with their endogenous ligands sequentially mediates the trafficking of DCs within the inflamed lung.

PMID: 23603910


Under inflammatory conditions such as allergic airway inflammation, Ly6Chigh monocytes differentiate into inflammatory antigen presenting dendritic cells (DCs) and are rapidly recruited from the circulation into the airway in a chemotactic cytokine receptor, CCR2, -dependent manner, presumably via interaction with a CCR2 ligand, CCL2, into the airway, where they mature and further traffic into draining lymph nodes to trigger T cell-mediated immune responses. However, our previous findings of a greatly reduced severity of allergic airway inflammation in Fpr2-/- mice characterized by diminished DC recruitment prompted us to investigate the relationship between CCR2 and Fpr2 in mediating inflammatory airway inflammation.

We found that the liquid collected from the airway of mice with asthmatic inflammation contained both the CCR2 ligand CCL2 and an Fpr2 agonist peptide, CRAMP. In CCR2-/- or CCL2-/- mice, very few Ly6Cmonocyte-derived inflammatory DCs are observed in the allergic inflammatory airway. In contrast, in Fpr2-/- or CRAMP-/- mice, inflammatory DCs accumulated in areas surrounding small blood vessels, but their further trafficking into the region surrounding small airways was diminished. We further found that monocyte-derived inflammatory DCs recruited into the inflamed lung via CCR2 lost functional CCR2 after encountering additional inflammatory stimulants, such as bacterial products that stimulate a group of pattern recognition receptors called Toll Like Receptors (TLRs) agonists, expressed elevated Fpr2, to complete the next step of trafficking to the inflamed small airway regions in response to the Fpr2 ligand, CRAMP. In the small airway regions, inflammatory DCs reduced their expression of Fpr2 but increased the expression of CCR7, which completes the final step of DC trafficking into the draining lymph nodes, where proper immune responses were initiated through presentation of antigens to T lymphocytes. Our study demonstrates that chemotaxis signal relay mediated by multiple cell surface receptors is essential for the trafficking of DCs during allergic airway inflammatory responses.


Acknowledgements: This project was supported in part with Federal funds from National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E and also in part by the Intramural Research Program of the NCI, NIH.



Drs. Keqiang Chen and Ji Ming Wang



Brian Daniels-Li