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Neutrophil GM-CSF receptor dynamics in acute lung injury.

Authors
  • De Alessandris, Silvia1
  • Ferguson, G John2
  • Dodd, Alison J2
  • Juss, Jatinder K1
  • Devaprasad, Abhinandan3
  • Piper, Siân2
  • Wyatt, Owen2
  • Killick, Helen2
  • Corkill, Dominic J2
  • Cohen, E Suzanne2
  • Pandit, Aridaman3
  • Radstake, Timothy R D J3
  • Simmonds, Rosalind1
  • Condliffe, Alison M1
  • Sleeman, Matthew A2
  • Cowburn, Andrew S1
  • Finch, Donna K2
  • Chilvers, Edwin R1
  • 1 Department of Medicine, University of Cambridge, Cambridge, United Kingdom. , (United Kingdom)
  • 2 Respiratory, Inflammation and Autoimmunity, MedImmune Ltd., Cambridge, United Kingdom. , (United Kingdom)
  • 3 Department of Rheumatology and Clinical Immunology and Laboratory of Translational Immunology, University Medical Centre, Utrecht, Netherlands. , (Netherlands)
Type
Published Article
Journal
Journal of Leukocyte Biology
Publisher
Wiley (John Wiley & Sons)
Publication Date
Jun 01, 2019
Volume
105
Issue
6
Pages
1183–1194
Identifiers
DOI: 10.1002/JLB.3MA0918-347R
PMID: 30942918
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

GM-CSF is important in regulating acute, persistent neutrophilic inflammation in certain settings, including lung injury. Ligand binding induces rapid internalization of the GM-CSF receptor (GM-CSFRα) complex, a process essential for signaling. Whereas GM-CSF controls many aspects of neutrophil biology, regulation of GM-CSFRα expression is poorly understood, particularly the role of GM-CSFRα in ligand clearance and whether signaling is sustained despite major down-regulation of GM-CSFRα surface expression. We established a quantitative assay of GM-CSFRα surface expression and used this, together with selective anti-GM-CSFR antibodies, to define GM-CSFRα kinetics in human neutrophils, and in murine blood and alveolar neutrophils in a lung injury model. Despite rapid sustained ligand-induced GM-CSFRα loss from the neutrophil surface, which persisted even following ligand removal, pro-survival effects of GM-CSF required ongoing ligand-receptor interaction. Neutrophils recruited to the lungs following LPS challenge showed initially high mGM-CSFRα expression, which along with mGM-CSFRβ declined over 24 hr; this was associated with a transient increase in bronchoalveolar lavage fluid (BALF) mGM-CSF concentration. Treating mice in an LPS challenge model with CAM-3003, an anti-mGM-CSFRα mAb, inhibited inflammatory cell influx into the lung and maintained the level of BALF mGM-CSF. Consistent with neutrophil consumption of GM-CSF, human neutrophils depleted exogenous GM-CSF, independent of protease activity. These data show that loss of membrane GM-CSFRα following GM-CSF exposure does not preclude sustained GM-CSF/GM-CSFRα signaling and that this receptor plays a key role in ligand clearance. Hence neutrophilic activation via GM-CSFR may play an important role in neutrophilic lung inflammation even in the absence of high GM-CSF levels or GM-CSFRα expression. ©2018 The Authors. Society for Leukocyte Biology Published by Wiley Periodicals, Inc.

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