Neutrophils restrain allergic airway inflammation by limiting ILC2 function and monocyte-dendritic cell antigen presentation
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
Neutrophil mobilization, recruitmentand clearancemust be tightly regulated asover-exuberant neutrophilic inflammation isimplicated in the pathology of chronic diseases, including asthma. Efforts to target neutrophilstherapeutically have failed to consider theirpleiotropic functions and theimplications of disrupting fundamental regulatory pathways that govern their turnover duringhomeostasisand inflammation.Using thehouse dust mite(HDM)model of allergic airways disease, we demonstrate that neutrophil depletion unexpectedly resulted in exacerbated TH2 inflammation, epithelial remodelling and airway resistance. Mechanistically, this was attributable to astriking increase insystemic G-CSF concentrations, which are ordinarily negatively regulated in the periphery by transmigrated lung neutrophils. Intriguingly, we found that increasedG-CSF augmented allergic sensitization in HDM exposed animals bydirectly acting on airway ILC2s toelicitcytokine 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 modelling the effects of neutrophil depletion, our studies have therefore 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.
Date Issued
2019-11-29
Date Acceptance
2019-09-24
Citation
Science Immunology, 2019, 4 (41), pp.1-18
ISSN
2470-9468
Publisher
American Association for the Advancement of Science
Start Page
1
End Page
18
Journal / Book Title
Science Immunology
Volume
4
Issue
41
Copyright Statement
© 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works http://www.sciencemag.org/about/science-licenses-journal-article-reuseThis is an article distributed under the terms of the Science Journals Default License.
Sponsor
Rosetrees Trust
Wellcome Trust
Wellcome Trust
British Medical Association
British Lung Foundation
Asthma UK
Medical Research Council (MRC)
Wellcome Trust
Grant Number
A1362
209458/Z/17/Z
209458/Z/17/Z
H C ROSCOE (2015) GRANT
PPRG15-9
AUK-IG-2014-286
MR/M01245X/1
107059/Z/15/Z
Subjects
Science & Technology
Life Sciences & Biomedicine
Immunology
COLONY-STIMULATING FACTOR
CXCR2 ANTAGONIST AZD5069
INNATE LYMPHOID-CELLS
SEVERE ASTHMA
MONOCLONAL-ANTIBODY
DOUBLE-BLIND
T-CELLS
G-CSF
GRANULOCYTE
SPUTUM
Animals
Antigen Presentation
Dendritic Cells
Female
Humans
Hypersensitivity
Immunity, Innate
Inflammation
Lymphocytes
Mice
Mice, Inbred BALB C
Monocytes
Neutrophils
Dendritic Cells
Neutrophils
Lymphocytes
Monocytes
Animals
Mice, Inbred BALB C
Humans
Mice
Hypersensitivity
Inflammation
Antigen Presentation
Female
Immunity, Innate
Publication Status
Published
Date Publish Online
2019-11-08