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

Format

Journal Article

Search for Full-text

Users with a NEOMED Library login can search for full-text journal articles at the following url: https://libraryguides.neomed.edu/home

Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

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 July 28, 2021, https://neomed.omeka.net/items/show/6781.

Social Bookmarking