Title: Chitinase-like proteins: the missing link in allergen-induced neutrophilic inflammation.
Funder: Asthma UK

Abstract: Severe asthma is often associated with neutrophila and IL-17-producing cells. Little is known about the triggers that make them the dominant cells in the inflamed airways of severe asthmatics, or how these cells contribute to pathology. Moreover, severe asthma is poorly controlled by commonly used therapies, with patients often becoming unresponsive/resistant to steroid treatments. Thus, there is a clear need to gain a better understanding of the fundamental principles behind the biology of neutrophil/Th17 airway inflammation and the development of severe asthma. We recently described a novel role for the family of chitinase-like proteins (CLPs) in driving alveolar neutrophil recruitment through increased IL-1/IL-18 expression and expansion of IL-17-producing γδ T cells. This was a surprising discovery considering CLP expression is strongly associated with type 2 inflammatory diseases not normally characterised by neutrophilia. This ability of CLPs to increase lung neutrophil numbers, combined with previously published data that shows increased CLP expression in asthmatics correlates with severe disease, suggests CLPs may be the “missing link” that tips the balance of airway inflammation towards neutrophil dominance. Further to effects on neutrophilia, CLPs also alter the production of type 2 cytokines during lung inflammation. As a consequence of increased pro-fibrotic IL-13 levels and also through direct, as yet undefined actions, CLPs will promote repair/remodelling of lung tissue, a dominant trait of severe asthma. Based on these findings, we propose that CLPs are key regulators of both innate and adaptive immune responses, pushing the boundaries of asthma pathology. We will use a combination of in vitro assays, in vivo CLP overexpression, and mouse models of chronic allergic airway inflammation (AAI) to address the role of CLPs during allergen-induced neutrophilia and remodelling. Chronic AAI is induced in laboratory mice through administration of a cocktail of clinically relevant allergens to confer a mixed Th1/Th2/Th17, steroid-resistant, inflammatory phenotype similar to severe asthma. Utilising a unique monoclonal, neutralising antibody against Ym1 (murine CLP) in comparison to transient overexpression of CLPs, we will ask 1) what the impact of Ym1 is on allergen-induced neutrophilia and remodelling, 2) whether inflammasome activation is a key mechanism for neutrophil accumulation or the development of AAI and finally 3) if and how CLPs link innate neutrophil responses to type 2 immunity. Importantly, where possible within the realm of this application, effects of murine CLPs will be directly compared to human CLPs. Specifically; we will use in vitro assays to assess inflammasome activation and changes to remodelling genes. This proposal aims to identify biological functions of CLPs that are critical to the development of chronic AAI and remodelling, particularly in the context of neutrophilic inflammation. The data generated will greatly enhance our knowledge of not only CLP function, but also key initiating immune mechanisms influencing AAI development. This will pave the way for future studies that aim toward pinpointing regions of the CLP molecules responsible for specific biological functions and the development of therapeutic agents relevant for the treatment of severe asthma and other lung pathologies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY