Gastrin-releasing peptide receptor (GRPR) mediates chemotaxis in neutrophils |
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Authors: | Czepielewski Rafael Sanguinetti Porto Bárbara Nery Rizzo Lucas Bortolotto Roesler Rafael Abujamra Ana Lúcia Pinto Larissa Garcia Schwartsmann Gilberto Cunha Fernando de Queiroz Bonorino Cristina |
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Affiliation: | Laboratory of Cellular and Molecular Immunology, Biomedical Research Institute (IPB), Pontifícia Universidade Católica do Rio Grande do Sul, 90610-900, Porto Alegre, RS, Brazil. |
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Abstract: | 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. |
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