1. Neutrophil GM-CSF receptor dynamics in acute lung injury
- Author
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Helen Killick, Siân C. Piper, Abhinandan Devaprasad, E. Suzanne Cohen, Alison J. Dodd, Donna K. Finch, Silvia De Alessandris, Jatinder K. Juss, Alison M. Condliffe, Matthew A. Sleeman, Dominic J. Corkill, Andrew S. Cowburn, Rosalind Simmonds, Timothy R D J Radstake, Aridaman Pandit, G. John Ferguson, Owen Wyatt, Edwin R. Chilvers, Finch, Donna K [0000-0003-1834-1260], and Apollo - University of Cambridge Repository
- Subjects
Lipopolysaccharides ,Male ,0301 basic medicine ,Guest Editors: Sylvain Bourgoin, Patrice Poubelle, and Patrick McDonald ,Time Factors ,CLEARANCE ,Neutrophils ,RESPIRATORY-DISTRESS-SYNDROME ,Cytokine Receptor Common beta Subunit ,Mice ,0302 clinical medicine ,Immunology and Allergy ,Internalization ,Receptor ,media_common ,Mice, Inbred BALB C ,medicine.diagnostic_test ,apoptosis ,Hematology ,COLONY-STIMULATING FACTOR ,Ligand (biochemistry) ,alveolar ,Receptors, Granulocyte-Macrophage Colony-Stimulating Factor ,1107 Immunology ,030220 oncology & carcinogenesis ,Female ,medicine.symptom ,Primary Research ,Pulmonary alveolar proteinosis ,signaling ,Life Sciences & Biomedicine ,Adult ,EXPRESSION ,LPS ,media_common.quotation_subject ,Acute Lung Injury ,Immunology ,Mice, Transgenic ,Inflammation ,Lung injury ,Biology ,Article ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Journal Article ,Animals ,Humans ,PULMONARY ALVEOLAR PROTEINOSIS ,MODULATION ,Science & Technology ,Cell Biology ,medicine.disease ,Colony-stimulating factor ,Pulmonary Alveoli ,ALPHA ,Disease Models, Animal ,030104 developmental biology ,Bronchoalveolar lavage ,Gene Expression Regulation ,inflammation ,NEUTROPHIL 2018, Quebec City, Canada, June 2–6 2018 ,RESPONSES - 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., GM‐CSF released during ALI stimulates neutrophil recruitment, induces down‐regulation of GM‐CSFR, and GM‐CSF consumption by neutrophils, yet sustained anti‐apoptotic signals require continued GM‐CSF stimulation.
- Published
- 2019