title: 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.affiliation: From the Laboratories of Molecular Immunoregulation and.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Chen
authors.affiliation: From the Laboratories of Molecular Immunoregulation and the Department of Pulmonary Medicine, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xiang
authors.affiliation: From the Laboratories of Molecular Immunoregulation and the College of Life Sciences and Bioengineering, School of Sciences, Beijing Jiaotong University, Beijing 100044, China.
authors.forename: Jiaqiang
authors.initials: J
authors.lastname: Huang
authors.affiliation: Leidos Biomedical Research, Inc., SAIC-Frederick, Frederick, Maryland 21702, and.
authors.forename: Wanghua
authors.initials: W
authors.lastname: Gong
authors.affiliation: From the Laboratories of Molecular Immunoregulation and.
authors.forename: Teizo
authors.initials: T
authors.lastname: Yoshimura
authors.affiliation: Experimental Immunology, Cancer and Inflammation Program and.
authors.forename: Qun
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: the Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702.
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.affiliation: the Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Le
authors.affiliation: From the Laboratories of Molecular Immunoregulation and wangji@mail.nih.gov.
authors.forename: Ji Ming
authors.initials: JM
authors.lastname: Wang
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D054421:Chemokine CCL21 / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D044042:Receptors, Formyl Peptide / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D054421:Chemokine CCL21; D000949:Histocompatibility Antigens Class II; D008070:Lipopolysaccharides; D044042:Receptors, Formyl Peptide; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C481578:formyl peptide receptor 2, mouse; D018664:Interleukin-12
keywords: CRAMP; Cellular Immune Response; Dendritic Cell; Fpr2; G Protein-coupled Receptor (GPCR); Immunology; Inflammation; Maturation