Background/Purpose: Understanding alterations of the immune homeostasis in individuals at risk of rheumatoid arthritis (RA) can be a key to achieve earlier diagnosis and prevention. As joint pain typically presents prior to RA onset, we analysed the levels of various pain-associated immune mediators in individuals at risk of RA and in early untreated disease. Our results indicated elevated CCL22 concentrations in both cohorts, as compared to healthy individuals, and therefore we analysed in detail the potential sources and effects of CCL22 in RA.

Methods: CCL22 levels were measured by ELISA in sera of individuals at risk of RA, in early untreated RA and in age- and sex- matched controls, as well as in the synovial fluid of RA patients. CCL22 modulation by cigarette smoking was studied in bronchoalveolar lavage (BAL) cells of healthy smokers. Spatial tissue transcriptomics and single cell RNA sequencing were used to evaluate CCL22 gene expression in the inflamed joints. CCL22 production was also analysed in different macrophage, osteoclast, and dendritic cell subsets in cell cultures. Expression of the CCL22 receptor CCR4 was studied by single cell RNAseq and flow cytometry in peripheral blood (PB) and synovial fluid (SF) mononuclear cells. The role of CCL22 in arthritis development was studied by using the CCR4 inhibitor C-021 in the murine collagen antibody induced arthritis (CAIA) model.

Results: We observed elevated serum CCL22 levels in individuals at risk for RA and in early untreated RA. One factor contributing to the increase of CCL22 appeared to be smoking, as reflected by higher CCL22 levels in smokers in the RA cohort and by a significant demethylation of the CCL22 gene in BAL cells isolated from a cohort of healthy smokers. CCL22 was also expressed in the inflamed joints, as suggested by spatial tissue transcriptomics, and CCL22 levels in SF correlated with the inflammatory cytokines M-CSF and GM-CSF. Both cytokines induced CCL22 release in cultured macrophages. PB and SF dendritic cells (DCs) appeared to be the most prominent producers of CCL22 in vitro, and by analysing single cell transcriptomics a particularly high CCL22 expression was detected in LAMP3-positive DCs in SF. CCR4 gene expression was observed in various CD4- and CD8-positive T cell populations, including regulatory T cells but also naïve, central memory, and subsets of activated and effector T cells, such as CXCL13-positive helper T cells. Apart from T cells, an effect of CCL22 on myeloid cell populations was suggested by an impaired IL-12 production in DCs, elevated IL-10 production in macrophages and reduced osteoclast differentiation in presence of C-021. Importantly, arthritis development was reduced in mice treated with C-021, in the CAIA model, suggesting an overall inflammatory role for CCL22 in RA development.

Conclusion: The increase of CCL22 concentrations prior and after RA onset and the decreased joint inflammation in CAIA mice treated with CCR4 inhibitor suggest important roles for this chemokine in arthritis development. Dendritic cell-derived CCL22 might help orchestrating DC-T cell interactions and CCL22 could contribute to macrophage and DC activation as well as the development of osteoclasts.

« Back to ACR Convergence 2024

ACR Meeting Abstracts - https://acrabstracts.org/abstract/role-of-the-chemokine-ccl22-in-rheumatoid-arthritis-development/