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Neutrophil GM-CSF receptor dynamics in acute lung injury

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Title: Neutrophil GM-CSF receptor dynamics in acute lung injury
Authors: De Alessandris, S
Ferguson, GJ
Dodd, AJ
Juss, JK
Devaprasad, A
Piper, S
Wyatt, O
Killick, H
Corkill, DJ
Cohen, ES
Pandit, A
Radstake, TRDJ
Simmonds, R
Condliffe, AM
Sleeman, MA
Cowburn, AS
Finch, DK
Chilvers, ER
Item Type: Journal Article
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.
Issue Date: Jun-2019
Date of Acceptance: 12-Mar-2019
URI: http://hdl.handle.net/10044/1/69356
DOI: https://doi.org/10.1002/JLB.3MA0918-347R
ISSN: 0741-5400
Publisher: Society for Leukocyte Biology
Start Page: 1183
End Page: 1194
Journal / Book Title: Journal of Leukocyte Biology
Volume: 105
Issue: 6
Copyright Statement: ©2019 The Authors. Society for Leukocyte Biology Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Keywords: Science & Technology
Life Sciences & Biomedicine
Cell Biology
Hematology
Immunology
alveolar
apoptosis
inflammation
LPS
signaling
COLONY-STIMULATING FACTOR
PULMONARY ALVEOLAR PROTEINOSIS
RESPIRATORY-DISTRESS-SYNDROME
EXPRESSION
CLEARANCE
ALPHA
INFLAMMATION
MODULATION
APOPTOSIS
RESPONSES
LPS
alveolar
apoptosis
inflammation
signaling
Immunology
1107 Immunology
Publication Status: Published
Online Publication Date: 2019-04-03
Appears in Collections:National Heart and Lung Institute