The tissue biology of inflammasomes

Thesis

Inflammasomes are tissue damage and infection sensing pathways in immune cells which, when overactive, contribute to immunopathology in diseases such as inflammatory arthritis. Using time-resolved single-cell RNA sequencing analyses of mouse inflammatory arthritis compared with human rheumatoid arthritis, spatial transcriptomics, and functional studies, we provide a view into the tissue biology of NLRP3 using rheumatoid arthritis as an exemplar of sterile tissue inflammation. We report that NLRP3 inflammasome expression and activity are kept low in all tissue-resident macrophage subsets. Myeloid sensing of normal apoptotic cell turnover, via efferocytosis receptors such as MERTK, contributes to low inflammasome activity in health. In disease, GM-CSFR+ recruited monocyte-derived macrophages home to the lining layer, drive most of NLRP3 and pro-IL-1β expression and contribute to inflammatory pain, which can be controlled by blocking GM-CSF in vivo. Therefore, current technologies allow us to move inflammasome research into the tissue context and explore their link with pathology and pain.

Authors: Chappell, GR

• DOI: 10.5287/ora-mz7xyd81b
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: rheumatoid arthritis; GM-CSF; NLRP3; inflammasome
• Subjects: Inflammasome; Granulocyte-macrophage colony-stimulating factor; Inflammation; Rheumatoid arthritis; Immunology; Interleukin-1