Neutrophil recruitment and function in the context of allergic asthma and associated viral exacerbations: opportunities and implications for therapeutic intervention
File(s)
Author(s)
Bruno, Nicoletta
Type
Thesis
Abstract
Neutrophils are present both in allergic and non-allergic forms of asthma and constitute a prominent inflammatory component in a subset of patients with severe disease. However, the mechanisms leading to the development of a neutrophilic response to allergen and the exact contribution of neutrophils to asthma pathophysiology are still poorly defined. The aim of this thesis was to elucidate the pathways underlying neutrophil recruitment in mouse models of allergic airway disease (AAD) and their relevance in the context of rhinovirus (RV)-induced allergic asthma exacerbations. Furthermore, it was investigated whether AAD can be ameliorated by targeting neutrophilic inflammation.
In Chapter 3, I demonstrated that three distinct inbred mouse strains (BALB/c, 129/S2 and C57BL/6 mice) presented with different magnitudes of pulmonary neutrophilia upon exposure to the aeroallergens house dust mite (HDM) and Alternaria alternata, with BALB/c mice displaying the greater neutrophil response. Inherent differences in the granulocytic response between mouse strains were utilised to probe the underlying pathways governing a neutrophilic response to allergen, highlighting a critical role for the IL-1β-IL-17A-G-CSF/ELR+CXC chemokine axis.
Studies conducted within the group had shown that depletion of neutrophils in HDM-exposed BALB/c mice, rather than being protective, actually resulted in augmented type 2 inflammation. In Chapter 4 of this thesis, I demonstrated that neutrophil depletion was accompanied by a reinforcement of the IL-1β-IL-17A-G-CSF pathway previously delineated, as a consequence of a loss of a negative feedback loop ordinarily imparted by neutrophils in the periphery. In this context, the elevated levels of G-CSF drove monocytosis and increased antigen presentation by monocyte-derived dendritic cells, whilst also potentiating early production of Th2 cytokines by ILC2s...
In Chapter 3, I demonstrated that three distinct inbred mouse strains (BALB/c, 129/S2 and C57BL/6 mice) presented with different magnitudes of pulmonary neutrophilia upon exposure to the aeroallergens house dust mite (HDM) and Alternaria alternata, with BALB/c mice displaying the greater neutrophil response. Inherent differences in the granulocytic response between mouse strains were utilised to probe the underlying pathways governing a neutrophilic response to allergen, highlighting a critical role for the IL-1β-IL-17A-G-CSF/ELR+CXC chemokine axis.
Studies conducted within the group had shown that depletion of neutrophils in HDM-exposed BALB/c mice, rather than being protective, actually resulted in augmented type 2 inflammation. In Chapter 4 of this thesis, I demonstrated that neutrophil depletion was accompanied by a reinforcement of the IL-1β-IL-17A-G-CSF pathway previously delineated, as a consequence of a loss of a negative feedback loop ordinarily imparted by neutrophils in the periphery. In this context, the elevated levels of G-CSF drove monocytosis and increased antigen presentation by monocyte-derived dendritic cells, whilst also potentiating early production of Th2 cytokines by ILC2s...
Version
Open Access
Date Issued
2023-01-11
Date Awarded
01/10/2023
Advisor
Snelgrove, Robert
Lloyd, Clare
Singanayagam, Aran
Sponsor
Asthma UK
Imperial College London
Wellcome Trust (London, England)
Grant Number
P67875_WHRL
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)