Impact of the alarmin Il-33 on neutrophilic inflammation in chronic lung disease

Blockade of the epithelial alarmin IL-33 is a novel treatment strategy in development for people with asthma, COPD and other chronic lung conditions like bronchiectasis.

IL-33 is released in response to epithelial damage such that caused by viral infection and triggers activation of multiple parts of the immune system. IL-33 signalling is believed to be very important during acute viral infections such as COVID-19 and influenza, and during exacerbations of chronic lung diseases.

Neutrophils are key mediators of the immune response to infection, but these innate immune cells can be dysfunctional or overactive in chronic inflammatory conditions. Animal studies suggest that IL-33 blockade reduces neutrophilic inflammation in the lungs but whether this is a direct or indirect effect is unknown. It is not even known if neutrophils express the receptor for IL-33, ST2, at sufficient levels to be responsive to IL-33, or whether neutrophils can respond to the oxidised form of IL-33 (oxIL-33) through the RAGE pathway, a recently described alternative signalling pathway for IL-33. Receptor expression will be investigated in blood and airway neutrophils.

Understanding whether IL-33 blockade can influence neutrophil responses in the lungs is important for understanding the role of IL-33 blocking monoclonal antibodies in disease.

In this project we will investigate the in-vitro and in-vivo impact of IL-33 blockade on neutrophilic inflammation. The project will involve culture of primary neutrophils and epithelial cells from people with chronic lung disease and healthy controls, cell stimulation with IL-33 followed by targeted assays and proteomics, and analysis of biological samples obtained from clinical trials in which patients are receiving anti-IL33 monoclonal antibodies. In addition to tissue culture, key laboratory techniques will include primary cell isolation, flow cytometry, immunohistochemistry and fluorescence microscopy, ELISA and functional assays.

The project will be most suited to a candidate keen to pursue a career in immunology, pharmacology and/or translational research involving patients.

The Respiratory research group at the University of Dundee is a world leading centre for translational research into inflammation and infection in respiratory disease. Previous PhD students have won multiple awards and students regularly published in high impact journals.

Start date is negotiable for the right candidate.

Informal enquiries to Professor James D Chalmers j.chalmers@dundee.ac.uk

To apply send CV and cover letter to respiratoryresearchgroup@dundee.ac.uk