The neuropeptide neuromedin U activates eosinophils and is involved in allergen-induced eosinophilia

Abstract

Neuromedin U (NMU) is a neuropeptide expressed not only in the central nervous system but also in various organs, including the gastrointestinal tract and lungs. NMU interacts with two G protein-coupled receptors, NMU-R1 and NMU-R2. Although NMU-R2 is expressed in a specific region of the brain, NMU-R1 is expressed in various peripheral tissues, including immune and hematopoietic cells. Our recent study demonstrated an important role of NMU in mast cell-mediated inflammation. In this study, we showed that airway eosinophilia was reduced in NMU-deficient mice in an allergen-induced asthma model. There were no differences in the antigen-induced Th2 responses between wild-type and NMU knockout mice. NMU-R1 was highly expressed in the eosinophil cell line, and NMU directly induced Ca(2+) mobilization and extracellular/signal-regulated kinase phosphorylation. NMU also induced cell adhesion to components of the extracellular matrix (fibronectin and collagen type I), and chemotaxis in vitro. Furthermore, NMU-R1 was also expressed in human peripheral blood eosinophils, and NMU induced cell adhesion in a dose-dependent manner. These data indicate that NMU promotes eosinophil infiltration into inflammatory sites by directly activating eosinophils. Our study suggests that NMU receptor antagonists could be novel targets for pharmacological inhibition of allergic inflammatory diseases, including asthma.

Neuromedin U: A Multifunctional Neuropeptide with Pleiotropic Roles

“…NmU mRNA has been detected in antigen-presenting cells, particularly monocytes and dendritic cells, and NMUR1 mRNA has been detected in T and natural killer cells, and also at lower concentrations in other immune and hematopoietic cells such as eosinophils and mast cells (14,122 ), suggesting a role in the immune response. NmU was first shown to induce synthesis and release of several different cytokines [interleukin-4 (IL-4), IL-5, IL-6, IL-10, and IL-13) from a mouse T-helper 2 cell line in an NMUR1-dependent fashion (123 ).…”

“…The fact that NmU is involved in secretion of proinflammatory cytokines explains its role as an inflammation promoter: local NmU administration induces progressive vasodilation and edema, while NmU-deficient mice show decreased extravasation mediated by substance P (122 ). Aside from localized inflammatory phenomena, mice deficient in NmU showed decreased mortality following lipopolysaccharide-induced septic shock, and this was due to reduced circulating IL-6 concentrations (124 ).…”

“…Binding of NmU to NMUR1 present in mast cells induced their degranulation, resulting in vasodilation, edema, and neutrophil infiltration (33 ). NmU was also shown to promote eosinophil activation, migration, and adhesion to inflammatory sites in a dose-dependent and NMUR1-mediated manner, thus suggesting a role for this peptide in allergic reactions (122 ). In spite of these effects being mediated by NMUR1, NmU-mediated inflammation has been shown to be unaffected in Nmur1 Ϫ/Ϫ mice (125 ).…”

The c-Myb target gene neuromedin U functions as a novel cofactor during the early stages of erythropoiesis

“…Because we and others have reported that NmU induces an intracellular calcium ion (Ca 2ϩ ) flux 14,17,25,26,30,31 and that mobilized Ca 2ϩ can directly activate the classic PKC-␤II isoform to modulate hematopoietic cell proliferation and differentiation, 32,33 we determined the ability of NmU to activate PKC-␤II. Using immunofluorescence microscopy, we observed PKC-␤II in the cytoplasm of unstimulated K562 ( Figure 4A) and CD34 ϩ cells ( Figure 4C).…”

“…16,18,21 In the gut, NmU has been reported to regulate local blood flow and ion transport. [22][23][24] Although NmU has been reported to stimulate cytokine production in the murine Th2-type T-cell clone D10.G4.1 25 and promote mast cell-mediated inflammation, 26 the physiologic function of NmU during hematopoiesis in the bone marrow remains ill defined. Given that c-Myb is required during erythropoiesis and that NmU is a candidate Myb target gene, we postulated that c-Myb induces NmU expression in normal hematopoietic cells to facilitate erythropoiesis.…”