Elucidating the Roles of CCL17 and CCL22 in Inflammatory Arthritis

Rheumatoid arthritis (RA) is a complex, autoimmune disease that targets the synovial joints. It is characterised by chronic and systemic inflammation and if left untreated, leads to debilitating pain, permanent cartilage degradation and bone erosion in the affected joints. There is no cure and while glucocorticoids reduce RA inflammation, their long-term use leads to adverse effects. How glucocorticoids induce their immunosuppressive effects remains to be fully elucidated. Various inflammatory mediators and cell types perpetuate this heterogeneous disease. C-C motif chemokine ligand 17 (CCL17) is upregulated by the pro-inflammatory cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF), and both are highly elevated in the synovial fluid of patients. GM-CSF induces CCL17 production in monocytes and macrophages via the epigenetic demethylase, Jumonji domain-containing 3 protein (JMJD3), and the transcription factor, interferon regulatory factor 4 (IRF4). CCL17 is similarly upregulated by interleukin 4 (IL4); however, this anti-inflammatory cytokine is present at low levels in RA patients. Together, GM-CSF and IL4 can generate dendritic cells in vitro. The pro-inflammatory CD1c+ dendritic cell subset is elevated in the synovium of RA patients, and while expression of this population correlates with RA disease activity and CCL17 levels, whether these cytokines induce CCL17 production by CD1c+ dendritic cells is unknown. CCL17 is one of two functional CCR4 ligands but, the role and regulation of the other ligand, CCL22, has not been explored in RA. In contrast to CCL17, CCL22 is constitutively expressed but its levels are decreased in the RA synovial fluid. GM-CSF and IL4 can induce CCL22 production but whether JMJD3 and IRF4 are needed for its regulation is undetermined, and whether CCL22 promotes or prevents inflammatory pain and disease remains unknown. In this PhD thesis, the role and regulation of CCL22 was investigated and compared to that of CCL17. Bo