Dissecting the phenotype and function of synovial tissue macrophages in health, active and remission RA

Finlay, Samuel Robert (2020) Dissecting the phenotype and function of synovial tissue macrophages in health, active and remission RA. PhD thesis, University of Glasgow.

Abstract

Rheumatoid arthritis (RA) is a chronic, inflammatory auto immune disease primarily affecting the joints, resulting in joint destruction. Despite improved therapeutics towards RA, the majority of patients do no achieve sustained clinical remission and are susceptible to flare. Synovial tissue macrophages (STMs) have been highlighted as a key cell mediator of disease pathogenesis in RA but their characteristics and functional role in health and in disease remission is not fully understood. The MerTK TAM receptor is one of the key receptors on tissue resident macrophages that regulates efferocytosis and inflammation. However, the role of MerTK in the biology of human synovial tissue macrophages was unknown.

Here we show that STMs in healthy tissue and sustained remission express significantly greater levels of MerTK on their surface than those in active disease. We also demonstrate that the MerTK/Gas6 pathway may play a functional protective role in the joint by reducing production of pro-inflammatory cytokines, specifically, by MerTK+ STMs in sustained remission. Inhibition of MerTK on monocyte-derived macrophages showed a significant impact on their interaction with synovial fibroblasts from active disease. Using a transwell non-direct co-culturing technique, MerTK inhibition in macrophages increased pro-inflammatory cytokines, chemokines and MMPs expression by FLS indicated that MerTK may play an important role in maintaining a homeostatic environment in the synovium. This development was further explored through bulk RNA sequencing of the fibroblasts from the co-cultures to uncover further indicators that may influence the pathology or protection of the synovium.
In summary, health and disease (RA) remission state is characterised by STMs expressing MerTK while MerTK negative macrophages are abundant in patients with active RA. MerTK expressing macrophage play regulatory role by limiting activation of synovial fibroblasts. Recent scRNA sequencing of STMs from healthy, undifferentiated arthritis, active RA and sustained clinical remission identified new clusters of STMs in MerTK negative and positive populations and these are currently explored in the lab.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Rheumatoid arthritis, macrophage, fibroblast. cytokines.
• Subjects: Q Science > QR Microbiology > QR180 Immunology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Funder's Name: Versus Arthritis (ARTRESUK)
• Supervisor's Name: Kurowska-Stolarska, Dr Mariola and Filer, Dr Andrew
• Date of Award: 2020
• Embargo Date: 15 May 2023
• Depositing User: Mr Sam Finlay
• Unique ID: glathesis:2020-81361
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 18 May 2020 11:08
• Last Modified: 18 May 2020 11:08
• URI: https://theses.gla.ac.uk/id/eprint/81361