Neutrophil elastase downmodulates native G-CSFR expression and granulocyte-macrophage colony formation
Title
Neutrophil elastase downmodulates native G-CSFR expression and granulocyte-macrophage colony formation
Creator
Piper M G; Massullo P R; Loveland M; Druhan L J; Kindwall-Keller T L; Ai J; Copelan A; Avalos B R
Publisher
Journal of Inflammation-London
Date
2010
2010-01
Description
Background: The granulocyte colony-stimulating factor receptor (G-CSFR) plays a critical role in maintaining homeostatic levels of circulating neutrophils (PMN). The mechanisms modulating G-CSFR surface expression to prevent chronic neutrophilia are poorly understood. Here, we report that neutrophil elastase (NE) proteolytically cleaves the G-CSFR on human PMN and blocks G-CSFR-mediated granulopoiesis in vitro. Methods: Human peripheral blood PMN isolated from healthy donors were incubated with NE. Expression of the G-CSFR was analyzed by flow cytometry and western blot analyses. Detection of G-CSFR cleavage products from the culture supernatants was also performed. Human bone marrow mononuclear cells were also cultured in the presence or absence of NE to determine its effects on the proliferation of granulocyte-macrophage colony forming units (CFU-GM). Results: Treatment of PMN with NE induced a time-dependent decrease in G-CSFR expression that correlated with its degradation and the appearance of proteolytic cleavage fragments in conditioned media. Immunoblot analysis confirmed the G-CSFR was cleaved at its amino-terminus. Treatment of progenitor cells with NE prior to culture inhibited the growth of granulocyte-macrophage colony forming units. Conclusions: These findings indicate that in addition to transcriptional controls and ligand-induced internalization, direct proteolytic cleavage of the G-CSFR by NE also downregulates G-CSFR expression and inhibits G-CSFRmediated granulopoiesis in vitro. Our results suggest that NE negatively regulates granulopoiesis through a novel negative feedback loop.
Subject
bone-marrow; cells; cyclic neutropenia; Immunology; leukocyte elastase; mobilization; myeloid-leukemia; progenitor; quantum proteolysis; severe congenital neutropenia; signal-transduction; stem cell; stimulating-factor-receptor
Identifier
Format
Journal Article
URL Address
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Pages
11-11
Volume
7
Citation
Piper M G; Massullo P R; Loveland M; Druhan L J; Kindwall-Keller T L; Ai J; Copelan A; Avalos B R, “Neutrophil elastase downmodulates native G-CSFR expression and granulocyte-macrophage colony formation,” NEOMED Bibliography Database, accessed April 19, 2024, https://neomed.omeka.net/items/show/6781.