Administration of Liposomal-Based Pde3b Gene Therapy Protects Mice Against Collagen-Induced Rheumatoid Arthritis via Modulating Macrophage Polarization

Abstract

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 Pde3b siRNA-loaded liposomes was assessed in a CIA model. To study the mechanism involved, we investigated the effect of Pde3b 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 Pde3b 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 Pde3b 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 Pde3b siRNA-loaded liposomes might serve as a promising therapeutic approach against RA.

Keywords:

• rheumatoid arthritis
• Pde3b
• liposomes
• macrophages

Data Sharing Statement

All data needed to evaluate the findings in this study are included in the manuscript and/or the Supplementary Information. Raw transcriptomic data have been deposited in the NCBI public repository Sequence Read Archive (Bioproject ID: PRJNA1025256, https://dataview.ncbi.nlm.nih.gov/object/PRJNA1025256?reviewer=5g2re1r4lpqegp5416eilve61p). Additional data related to this paper are available from the corresponding author upon request.

Acknowledgments

We thank Xin Wang, Yan Wang, and Yuan Sun from Institute of Hydrobiology, Chinese Academy of Sciences for technical assistance in micro-CT analysis and in vivo imaging system.

Disclosure

The authors declare that they have no conflict of interest.

Additional information

Funding

Our study was supported by the National Natural Science Foundation of China (82300929 and 82100892), Department of Science and Technology of Hubei Province Program Project (2022CFB739), the Intramural Research Program of the Central Hospital of Wuhan (21YJ01, 23YJ14), and Wuhan Talent Project.