The formylpeptide receptor 2 (Fpr2) and its endogenous ligand cathelin-related antimicrobial peptide (CRAMP) promote dendritic cell maturation.

Abstract

Mouse formylpeptide receptor 2 (Fpr2) is a homologue of the human G-protein coupled chemoattractant receptor FPR2, which interacts with pathogen and host-derived chemotactic agonists. Our previous studies revealed reduced allergic airway inflammation and immune responses in Fpr2-deficient (Fpr2(-/-)) mice in association with diminished dendritic cell (DC) recruitment into the airway and draining lymph nodes. These defects prompted us to investigate the potential changes in the differentiation and maturation of DCs caused by Fpr2 deficiency. Bone marrow monocytes from Fpr2(-/-) mouse mice incubated with GM-CSF and IL-4 in vitro showed normal expression of markers of immature DCs. However, upon stimulation with the TLR4 agonist LPS, Fpr2(-/-) mouse DCs failed to express normal levels of maturation markers with reduced production of IL-12 and diminished chemotaxis in response to the DC homing chemokine CCL21. Fpr2(-/-) DCs also failed to induce allogeneic T-cell proliferation in vitro, and their recruitment into the T-cell zones of the spleen was reduced after antigen immunization. The capacity of Fpr2 to sustain normal DC maturation was dependent on its interaction with an endogenous ligand CRAMP expressed by DCs, because neutralization of either Fpr2 or CRAMP inhibited DC maturation in response to LPS. We additionally observed that the presence of exogenous CRAMP in culture increased the sensitivity of WT mouse DCs to LPS stimulation. The importance of CRAMP for DC maturation was further demonstrated by the observations that DCs from CRAMP(-/-) mice expressed lower levels of costimulatory molecules and MHC II and exhibited poor chemotaxis in response to CCL21 after LPS stimulation. Our observations indicate a nonredundant role for Fpr2 and its agonist CRAMP in DC maturation in immune responses.

• Authors: Keqiang Chen, Yi Xiang, Jiaqiang Huang, Wanghua Gong, Teizo Yoshimura, Qun Jiang, Lino Tessarollo, Yingying Le, Ji Ming Wang
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 25 Pg. 17553-63 (Jun 20 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 24808174 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Antimicrobial Cationic Peptides
• Cathelicidins
• Chemokine CCL21
• Histocompatibility Antigens Class II
• Lipopolysaccharides
• Receptors, Formyl Peptide
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• formyl peptide receptor 2, mouse
• Interleukin-12

Topics

• Animals
• Antimicrobial Cationic Peptides
• Cathelicidins (genetics, metabolism)
• Cell Line
• Cell Proliferation (drug effects)
• Chemokine CCL21 (genetics, metabolism)
• Dendritic Cells (cytology, metabolism)
• Histocompatibility Antigens Class II (genetics, metabolism)
• Humans
• Interleukin-12 (genetics, metabolism)
• Lipopolysaccharides (pharmacology)
• Mice
• Mice, Knockout
• Monocytes (cytology, metabolism)
• Receptors, Formyl Peptide (genetics, metabolism)
• T-Lymphocytes (cytology, metabolism)
• Toll-Like Receptor 4 (agonists, genetics, metabolism)