Gastrin-releasing peptide receptor (GRPR) mediates chemotaxis in neutrophils.
Neutrophil migration to inflamed sites is crucial for both the initiation of inflammation and resolution of infection, yet these cells are involved in perpetuation of different chronic inflammatory diseases. Gastrin-releasing peptide (GRP) is a neuropeptide that acts through G protein coupled receptors (GPCRs) involved in signal transmission in both central and peripheral nervous systems. Its receptor, gastrin-releasing peptide receptor (GRPR), is expressed by various cell types, and it is overexpressed in cancer cells. RC-3095 is a selective GRPR antagonist, recently found to have antiinflammatory properties in arthritis and sepsis models. Here we demonstrate that i.p. injection of GRP attracts neutrophils in 4 h, and attraction is blocked by RC-3095. Macrophage depletion or neutralization of TNF abrogates GRP-induced neutrophil recruitment to the peritoneum. In vitro, GRP-induced neutrophil migration was dependent on PLC-β2, PI3K, ERK, p38 and independent of Gαi protein, and neutrophil migration toward synovial fluid of arthritis patients was inhibited by treatment with RC-3095. We propose that GRPR is an alternative chemotactic receptor that may play a role in the pathogenesis of inflammatory disorders.
Laboratory of Cellular and Molecular Immunology, Biomedical Research Institute (IPB), Pontifícia Universidade Católica do Rio Grande do Sul, 90610-900, Porto Alegre, RS, Brazil.
Rafael Sanguinetti
RS
Czepielewski
Bárbara Nery
BN
Porto
Lucas Bortolotto
LB
Rizzo
Rafael
R
Roesler
Ana Lúcia
AL
Abujamra
Larissa Garcia
LG
Pinto
Gilberto
G
Schwartsmann
Fernando de Queiroz
Fde Q
Cunha
Cristina
C
Bonorino
D000704:Analysis of Variance; D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D019886:Gastrin-Releasing Peptide / Q000008:administration & dosage / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D010446:Peptide Fragments / Q000494:pharmacology; D018004:Receptors, Bombesin / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism*
D016207:Cytokines; D010446:Peptide Fragments; D018004:Receptors, Bombesin; C071363:bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-; D019886:Gastrin-Releasing Peptide; D001839:Bombesin