Investigating IL-36 receptor signalling in COPD: a novel drug target
File(s)
Author(s)
Owles, Harriet
Type
Thesis
Abstract
Chronic pulmonary obstructive disease (COPD) is a chronic inflammatory lung condition and leading cause of mortality and morbidity worldwide. Currently there are no treatments licenced for COPD that slow or reverse disease progression.
Interleukin (IL)-36 receptor signalling promotes neutrophilic inflammation in COPD. There is increased IL-36 receptor agonist (IL-36gamma) is released by small airway epithelial cells (SAEC) and causes small airway fibroblasts (SAF) to release neutrophil chemoattractants (CXCL1, CXCL8). Macrophages are a key inflammatory cell in COPD. This thesis shows that IL-36 gamma directly inhibits COPD macrophage phagocytosis of H. influenzae. Meanwhile the effect of IL-36 gamma on SAF causes healthy and COPD macrophages to be more pro-inflammatory. Respiratory viruses stimulate IL-36 gamma release from SAECs.
Thus, IL-36 gamma may drive virally induced exacerbations and secondary bacterial infections. Lung macrophages are a major source of IL-36RA. This thesis shows that COPD monocytes are innately different to healthy monocytes and have reduced IL-36RA mRNA (IL-36RN) expression. In healthy cells there is significant upregulation of IL-36RN from monocytes to GM-CSF differentiated macrophages, but this is not seen in COPD monocytes. As such IL-36RN is almost 2-fold higher in healthy GM-MDM compared to COPD GM-MDM. This study shows that phosphoinositide-3-kinase (PI3K) activity controls IL-36RN expression; PI3K is increased in COPD monocytes and macrophages and thus in vitro IL-36RN expression is likely further suppressed.
Nasosorption is a non-invasive sampling technique of the nasal epithelial lining fluid, previously used in asthma, allergy and viral illness studies. This is the first study using nasosorption in COPD patients. Eotaxin-1 is raised in COPD, especially those with high blood eosinophil counts: it should be studied further as a potential biomarker for TH2 inflammation in COPD. IL-36α, IL-36β and IL-36γ were all present at relatively high concentrations, but with no difference between COPD and controls. IL-36 agonist levels...
Interleukin (IL)-36 receptor signalling promotes neutrophilic inflammation in COPD. There is increased IL-36 receptor agonist (IL-36gamma) is released by small airway epithelial cells (SAEC) and causes small airway fibroblasts (SAF) to release neutrophil chemoattractants (CXCL1, CXCL8). Macrophages are a key inflammatory cell in COPD. This thesis shows that IL-36 gamma directly inhibits COPD macrophage phagocytosis of H. influenzae. Meanwhile the effect of IL-36 gamma on SAF causes healthy and COPD macrophages to be more pro-inflammatory. Respiratory viruses stimulate IL-36 gamma release from SAECs.
Thus, IL-36 gamma may drive virally induced exacerbations and secondary bacterial infections. Lung macrophages are a major source of IL-36RA. This thesis shows that COPD monocytes are innately different to healthy monocytes and have reduced IL-36RA mRNA (IL-36RN) expression. In healthy cells there is significant upregulation of IL-36RN from monocytes to GM-CSF differentiated macrophages, but this is not seen in COPD monocytes. As such IL-36RN is almost 2-fold higher in healthy GM-MDM compared to COPD GM-MDM. This study shows that phosphoinositide-3-kinase (PI3K) activity controls IL-36RN expression; PI3K is increased in COPD monocytes and macrophages and thus in vitro IL-36RN expression is likely further suppressed.
Nasosorption is a non-invasive sampling technique of the nasal epithelial lining fluid, previously used in asthma, allergy and viral illness studies. This is the first study using nasosorption in COPD patients. Eotaxin-1 is raised in COPD, especially those with high blood eosinophil counts: it should be studied further as a potential biomarker for TH2 inflammation in COPD. IL-36α, IL-36β and IL-36γ were all present at relatively high concentrations, but with no difference between COPD and controls. IL-36 agonist levels...
Version
Open Access
Date Issued
2025-06-05
Date Awarded
2026-03-01
Copyright Statement
Attribution-NonCommercial 4.0 International Licence (CC BY-NC)
License URL
Advisor
Donnelly, Louise
Elkin, Sarah
Barnes, Peter
Sponsor
Boehringer Ingleheim UK and Ireland (Firm)
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)