Administration of Liposomal-Based Gene Therapy Protects Mice Against Collagen-Induced Rheumatoid Arthritis via Modulating Macrophage Polarization.

BACKGROUND

Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease characterized by synovial inflammation and joint destruction. Despite progress in RA therapy, it remains difficult to achieve long-term remission in RA patients. Phosphodiesterase 3B (Pde3b) is a member of the phosphohydrolyase family that are involved in many signal transduction pathways. However, its role in RA is yet to be fully addressed.

METHODS

Studies were conducted in arthritic DBA/1 mice, a suitable mouse strain for collagen-induced rheumatoid arthritis (CIA), to dissect the role of Pde3b in RA pathogenesis. Next, RNAi-based therapy with siRNA-loaded liposomes was assessed in a CIA model. To study the mechanism involved, we investigated the effect of knockdown on macrophage polarization and related signaling pathway.

RESULTS

We demonstrated that mice with CIA exhibited upregulated Pde3b expression in macrophages. Notably, intravenous administration of liposomes loaded with siRNA promoted the macrophage anti-inflammatory program and alleviated CIA in mice, as indicated by the reduced inflammatory response, synoviocyte infiltration, and bone and cartilage erosion. Mechanistic study revealed that depletion of increased cAMP levels, by which it enhanced PKA-CREB-C/EBPβ pathway to transcribe the expression of anti-inflammatory program-related genes.

CONCLUSION

Our results support that Pde3b is involved in the pathogenesis of RA, and siRNA-loaded liposomes might serve as a promising therapeutic approach against RA.