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

Keqiang Chen,Mingyong Liu,Ying Liu,Chunyan Wang,Teizo Yoshimura,Wanghua Gong,Yingying Le,Lino Tessarollo,Ji Ming Wang

doi:10.1074/jbc.m113.450635

Abstract

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.

Highlights

Chemoattractant receptor Fpr2 interacts with host-derived agonists and mediates leukocyte trafficking
Reduced Recruitment of Monocyte-derived Inflammatory dendritic cell (DC) into the Inflamed Airway in Fpr2Ϫ/Ϫ Mice—We first investigated the identity of the receptors required for the accumulation of CD11cϩMHC IIϩ cells in the airway in the secondary immune responses to the inhalation of OVA combined with a low dose of LPS in mice after systemic antigen immunization with OVA (22) CD11cϩMHC IIϩ cells were increased in the lungs of WT mice immunized with OVA as compared with their naïve state (Fig. 1, A–D)
Reduced CCR2ϩ Population in Inflammatory DCs in the Inflamed Airway of Fpr2Ϫ/Ϫ Mice—Because the chemokine receptors CCR2, CCR5, and CCR6 have been implicated in the recruitment of Ly6Cϩ inflammatory DCs from the blood to inflamed tissues (3, 7), we examined the frequency of CCR2ϩ, CCR5ϩ, and CCR6ϩ cells in the Ly6CϩCD11cϩ cell population in the lung of mice with allergic airway inflammation

Summary

Background

Chemoattractant receptor Fpr interacts with host-derived agonists and mediates leukocyte trafficking. Results: In the lung of allergic inflammation, chemokine receptor CCR2 elicits accumulation of monocyte-derived DC in perivascular region, but Fpr is critical for cell trafficking to peribronchiolar area. A chemokine receptor CCR2 was implicated in mediating monocyte-derived dendritic cell (DC) recruitment into the lung, we previously discovered reduced accumulation of DCs in the inflamed lung in mice deficient in formylpeptide receptor Fpr (Fpr2؊/؊). Fpr, was shown to mediate neutrophil accumulation in the core of injury in response to tissue-derived agonists, subsequent to the initial recruitment of the cells to the peripheral regions of the injury by chemokine receptors (12). We demonstrate that Fpr and its endogenous ligand CRAMP play an important role in the accumulation of inflammatory DCs in the peribronchiolar tissues subsequent to CCR2-mediated cell trafficking into the perivascular regions in allergic airway

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION