GM-CSF instigates a dendritic cell–T-cell inflammatory circuit that drives chronic asthma development
Abstract
Background
Steroid-resistant asthma is often characterized by high levels of neutrophils and mixed TH2/TH17 immune profiles. Indeed, neutrophils are key drivers of chronic lung inflammation in multiple respiratory diseases. Their numbers correlate strongly with disease severity, and their presence is often associated with exacerbation of chronic lung inflammation.
Objective
What factors drive development of neutrophil-mediated chronic lung disease remains largely unknown, and we sought to study the role of GM-CSF as a potential regulator in chronic asthma.
Methods
Different experimental animal models of chronic asthma were used in combination with alveolar macrophage-reconstitution of global GM-CSF receptor knockout mice as well as cell-type–specific knockout animals to elucidate the role of GM-CSF signaling in chronic airway inflammation.
Results
We identify GM-CSF signaling as a critical factor regulating pulmonary accumulation of neutrophils. We show that although being not required for intrinsically regulating neutrophil migration, GM-CSF controls lung dendritic cell function, which in turn promotes T-cell–dependent recruitment of neutrophils to the airways. We demonstrate that GM-CSF regulates lung dendritic cell antigen uptake, transport, and TH2/TH17 cell priming in an intrinsic fashion, which in turn drives pulmonary granulocyte recruitment and contributes to development of airway hyperresponsiveness in chronic disease.
Conclusions
We identify GM-CSF as a potentially novel therapeutic target in chronic lung inflammation, describing a GM-CSF–dependent lung conventional dendritic cell-T-cell-neutrophil axis that drives chronic lung disease. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000473003Publication status
publishedExternal links
Journal / series
Journal of Allergy and Clinical ImmunologyVolume
Pages / Article No.
Publisher
ElsevierSubject
Neutrophils; Asthma; Chronic airway inflammation; GM-CSF; Dendritic cellOrganisational unit
03596 - Kopf, Manfred / Kopf, Manfred
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