An investigation of house dust mite proteases and their effect on calcium signalling and pro-inflammatory responses in asthma

Abstract

Allergic asthma caused by house dust mites (HDM) is highly prevalent and has links to the onset and exacerbation of asthma symptoms and the induction of an IgE-mediated immune response. HDM allergens contain proteolytic activities, including serine proteases such as trypsin-like proteases (TLPs) and chymotrypsin-like proteases (CTLPs), as well as cysteine proteases, which can interfere with various cellular functions. The aim of this study is to explore the impact of house dust mites (HDM) and its protease components on asthma epithelium, specifically focusing on their effect on calcium signalling and pro-inflammatory responses in asthmatic human primary bronchial epithelial cells (hPBECs). We discovered that HDM proteases, particularly serine proteases, activate protease-activated receptors (PARs) associated calcium signalling and lead to increased expression of pro-inflammatory alarmins, such as Interleukin 33 (IL-33) and thymic stromal lymphopoietin (TSLP). Furthermore, in a differentiated culture model of asthma hPBECs, we observed HDM-induced calcium mobilization involved PAR-2 and PAR-4 activation, as well as plasma membrane calcium channels from transient receptor potential vanilloid family TRPV1 and TRPV2. This study also explored the impact of HDM and HDM proteases on macrophage-like THP-1 cells, demonstrating increased secretion of pro-inflammatory cytokines and chemokines including IL-10, IL-6, Cxcl1 chemokine (CXC motif) ligand 1(CXCL1), tumour necrosis factor alpha (TNF-α), IL-8, along with elevated CTLPs activities and matrix metalloproteinase-9 (MMP-9), active-matrix metalloproteinase-2 (MMP-2) activities in cell condition media of macrophage-like THP-1 cells. Taken together, this study enhances our knowledge of the role of serine proteases in HDM-induced inflammation and regulation of ion channel function in asthma.

Thesis is embargoed until 31 July 2026

Date of Award	03 Jul 2023
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Chinese Scholarship Council (CSC)
Supervisor	Lorraine Martin (Supervisor), Lorcan McGarvey (Supervisor) & James Reihill (Supervisor)