Unravelling the roles of CRTH2+ cells in asthma pathogenesis

Thesis

Prostaglandin D2 (PGD2) receptor 2 (as known as chemoattractant receptor homologous to the T helper 2 cell, CRTH2) is expressed on various human immune cells including but not limited to type 2 helper T (Th2) cell, type 2 cytotoxic T (Tc2) cell, group 2 innate lymphoid cell (ILC2), eosinophil and basophil. These CRTH2+ cells are highly associated with type 2 (T2) immune response, the severity and the endotype of asthma. In this research, I demonstrated the importance of three types of CRTH2+ cells, Tc2 cells, basophils, and eosinophils, in inflammation and asthma. PGD2 induced cell migration, adhesion and survival, evoked the production of proinflammatory cytokine and fibrotic factors, and mediated autocrine/paracrine production of PGD2 in cultured human Tc2 cells. Using the CRTH2-specific antagonist fevipiprant as a tool, I observed the inhibition of the aforementioned PGD2-mediated activities in vitro, suggesting the anti-inflammatory and anti-fibrotic roles of CRTH2 antagonism in asthma. In the second study, the numbers of basophils that highly express CRTH2 were found to be significantly increased in blood and sputum from patients with severe eosinophilic asthma. Chemotaxis, interleukin (IL)-4/IL-13 production, granule histamine release and CD63/CD203c expression in basophils could be induced by PGD2, which could be suppressed by CRTH2 antagonism. The RNA sequencing revealed potential unique roles of the PGD2-CRTH2 pathway in basophils. In the third study, blood eosinophils from patients with eosinophilic asthma showed increased responses to the inducers of chemotaxis and degranulation ex vivo and in vitro, compared to those from non-eosinophilic asthma and healthy subjects. These enhanced responses were reversed after treatment with the anti-IL-5 monoclonal antibody mepolizumab. Mepolizumab also repressed the phosphorylation level of AKT, MERK and p38 in blood eosinophils, which was confirmed with single-cell RNA sequencing. These findings provided a better understanding of the roles of CRTH2+ cells in the pathogenic mechanisms of asthma.

Authors: Chen, W

• DOI: 10.5287/ora-1ajm1oz15
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: fevipiprant; CRTH2; Tc2; basophil; mepolizumab; prostaglandin D2; eosinophil; IL-5; asthma