Rheumatoid arthritis (RA) is characterized by joint inflammation and bone erosion mediated by excessive production of pro-inflammatory mediators. A new study highlights the importance of the chemokine CCL21 and cross-talk between macrophages and T cells in this destructive process.

Credit: Springer Nature Limited

In characterizing the pathogenic function of CCL21, the researchers found that the expression of its receptor CCR7 on monocytes was higher in patients with RA than in healthy individuals, and correlated with the patient’s 28-joint disease activity score (DAS28).

In vitro, monocyte chemotaxis, induced by treatment with synovial fluid from patients with RA, was reduced by neutralization of CCL21 or CCR7. Furthermore, treatment with CCL21 promoted the chemotactic activity of monocytes in a CCR7-dependent manner and upregulated the transcription of IL-6 and IL-23 (cytokines involved in T helper 17 (TH17) cell differentiation).

Given the important function of TH17 cells and IL-17 production in RA, the researchers assessed the effects of CCL21 on T cells in vitro. CCL21 treatment promoted IL-17 secretion by peripheral blood mononuclear cells (PBMCs), but not by T cells alone. Furthermore, CCL21 treatment promoted osteoclastogenesis by PBMCs, which was inhibited by antibodies against IL-6 receptor (IL-6R), IL-23 or IL-17.

These findings together suggest that CCL21 induces polarization of TH17 cells in a myeloid cell-dependent manner, which in turn stimulates osteoclast formation and bone erosion. Notably, adenovirus-mediated expression of CCL21 (via intra-articular injection) promoted joint inflammation and bone erosion in wild-type mice but not in CCR7-deficient mice.

CCL21 induces polarization of TH17 cells in a myeloid cell-dependent manner

“As a chemokine that attracts both T cells and macrophages, promotes myeloid and T cell pathogenic activity and is an RA susceptibility gene, CCL21 is ideally positioned to instigate disease and thus makes for a promising novel therapeutic target,” explains Katrien Van Raemdonck, first author of the study. “Further research will have to verify whether CCL21–CCR7 activity can be inhibited efficiently and safely for therapeutic purposes.”