Background: Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease characterized by pain, swelling, and stiffness in the joints. The pathological joint inflammation in RA is associated with the upregulation of C-X-C motif chemokine ligand 12 (CXCL12), also known as stromal cell-derived factor-1α (SDF-1α). CXCL12 plays a critical role in promoting inflammation by creating a chemokine gradient that facilitates T-cell migration and subsequent immune activation. C-X-C chemokine receptor type 7 (CXCR7) functions as a scavenger receptor for CXCL12, thereby modulating and potentially reducing inflammatory responses.

Objectives: We have developed a CXCR7-selective agonist with high specificity and potency for the CXCR7 receptor. In this study, we investigate the therapeutic potential of this novel CXCR7 agonist in the collagen-induced arthritis (CIA) mouse model, a widely used experimental model for RA.

Methods: In the collagen II induced arthritis (CIA) model, the male DBA/1 mice were divided into 5 groups: sham, model vehicle group, IL21120033 (30 and 60 mg/kg), ABT494 as positive control group. Except for sham group, the other mice were subcutaneously injected with 50 μL of the collagen-CFA at the base of the tail, 2-3 cm from the body under anesthesia (Day 0). Three weeks later, collagen-CFA emulsion was injected for booster immunization (Day 21). The treatment was initiated on Day 22 with oral dosing for 4 weeks. Clinical arthritic scoring and paw swelling assessments were performed twice a week. Daily until Day 28. At the end, the X-ray examination of the hind paw and the serum collection for cytokines were performed. After the serum collection, the inguinal and axillary lymph nodes were harvested for FACS assay and the hind paws were prepared for histopathology and immunohistochemistry (IHC) staining to analyze CXCR4 and CXCL12.

Results: The model vehicle group showed a gradual increase in arthritic scores, X-ray scores, inflammatory cell infiltration, and destruction of bone and cartilage compared to the normal sham group. However, IL21120033 at doses of 30 mg/kg and 60 mg/kg significantly reduced arthritic scores and inflammatory cell infiltration while alleviating bone and cartilage destruction. Immunohistochemistry analysis revealed that IL21120033 decreased CXCR4 and CXCL12 expression in the joints compared to the vehicle group. FACS analysis showed that IL21120033 dose-dependently increased CXCR4⁺ T cells in the lymph nodes, unlike the other groups. This suggests that IL21120033 inhibits the migration of CXCR4⁺ T cells from the lymph nodes to inflamed joint tissue.

Conclusion: IL21120033 demonstrated strong anti-rheumatoid arthritis (RA) efficacy by reducing CXCL12 levels and subsequently inhibiting CXCR4⁺ T cell migration into the joints of CIA mice. These findings identify IL21120033 as the first CXCR7 agonist to show significant efficacy in an animal model of rheumatoid arthritis.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.