Increased CCL22 production in early rheumatoid arthritis development with potential impact on mucosal autoimmunity, joint inflammation and T cell recruitment to LAMP3+ dendritic cells

Abstract

Objectives Understanding alterations in immune homeostasis can help early diagnosis and prevention in rheumatoid arthritis (RA). As joint pain often precedes RA onset, we analysed pain-associated immune mediators in individuals at risk of RA (RISK-RA) and in early untreated RA. Serum CCL22 levels were elevated in both groups, prompting us to further study its sources and effects in RA. Methods CCL22 expression was examined in RISK-RA and RA cohorts, healthy controls, BAL cells of healthy smokers and cigarette smoke-exposed mice. Spatial transcriptomics, single-cell RNA sequencing, and flow cytometry were used to assess CCL22 and CCR4 expression in joints. The CCR4 inhibitor C-021 was evaluated in collagen antibody-induced arthritis (CAIA). Results Increased CCL22 levels were detected in current smokers, in all tested cohorts, and in cigarette-smoke exposed mice. Smoking was associated with CCL22 gene hypomethylation in BAL cells. CCL22 was also expressed in arthritic joints, potentially induced by inflammatory mediators such as M-CSF and GM-CSF. ScRNA-seq and synovial fluid cell analyses identified LAMP3+CCR7+ dendritic cells (DCs) as the most prominent producers of CCL22. CCR4 was expressed by Tregs and subsets of activated, proliferating and effector CD4 + T cells. Beyond T cells, CCL22 may affect innate mechanisms as CCR4 inhibition altered cytokine expression in macrophages and DCs and decreased CAIA severity. Conclusions CCL22-mediated T cell recruitment may contribute to the mucosal breach of tolerance in smokers. In joints, CCL22 could promote inflammation and recruit activated and regulatory T cells to LAMP3+ DCs, a subset characterised by robust T cell modulatory potential.

Abstract of "Increased CCL22 production in early rheumatoid arthritis development with potential impact on mucosal autoimmunity, joint inflammation and T cell recruitment to LAMP3+ dendritic cells" by Filipović M, Afonso M, Argyriou A et al., https://doi.org/10.1016/j.jaut.2026.103633, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.