Neutrophils restrain allergic airway inflammation by limiting ILC2 function and monocyte–dendritic cell antigen presentation
Open Access
- 9 November 2019
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Immunology
- Vol. 4 (41)
- https://doi.org/10.1126/sciimmunol.aax7006
Abstract
Neutrophil mobilization, recruitment, and clearance must be tightly regulated as overexuberant neutrophilic inflammation is implicated in the pathology of chronic diseases, including asthma. Efforts to target neutrophils therapeutically have failed to consider their pleiotropic functions and the implications of disrupting fundamental regulatory pathways that govern their turnover during homeostasis and inflammation. Using the house dust mite (HDM) model of allergic airway disease, we demonstrate that neutrophil depletion unexpectedly resulted in exacerbated T helper 2 (TH2) inflammation, epithelial remodeling, and airway resistance. Mechanistically, this was attributable to a marked increase in systemic granulocyte colony-stimulating factor (G-CSF) concentrations, which are ordinarily negatively regulated in the periphery by transmigrated lung neutrophils. Intriguingly, we found that increased G-CSF augmented allergic sensitization in HDM-exposed animals by directly acting on airway type 2 innate lymphoid cells (ILC2s) to elicit cytokine production. Moreover, increased systemic G-CSF promoted expansion of bone marrow monocyte progenitor populations, which resulted in enhanced antigen presentation by an augmented peripheral monocyte-derived dendritic cell pool. By modeling the effects of neutrophil depletion, our studies have uncovered previously unappreciated roles for G-CSF in modulating ILC2 function and antigen presentation. More broadly, they highlight an unexpected regulatory role for neutrophils in limiting TH2 allergic airway inflammation.Keywords
Funding Information
- European Commission Directorate-General for Research and Innovation (FP7-PEOPLE-2013-IEF No627374)
- Wellcome (209458/Z/17/Z)
- Wellcome (107059/Z/15/Z)
- Medical Research Council (MR/M01245X/1)
- Cancer Research UK (A23983)
- British Lung Foundation (PPRG15-9)
- British Medical Association (HC Roscoe 2015 grant)
- Rosetrees Trust (M612)
- Cancer Research UK (A17196)
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