Semaphorin 6D Alleviates Osteoarthritis by Inhibiting NLRP3 Inflammasome Activation and Endoplasmic Reticulum Stress

Area of Science:

• Immunology
• Molecular Biology
• Rheumatology

Background:

• Osteoarthritis (OA) is a prevalent degenerative joint disease affecting over 500 million people worldwide.
• Synovial inflammation, driven by macrophage polarization and inflammasome activation, is a key factor in OA progression, exacerbating cartilage degradation.
• Targeting macrophage activity presents a promising therapeutic strategy for OA management.

Purpose of the Study:

• To investigate the regulatory role of SEMA6D in macrophage polarization.
• To assess the therapeutic potential of SEMA6D in osteoarthritis.
• To explore SEMA6D's impact on NLRP3 inflammasome activation and endoplasmic reticulum stress in OA.

Main Methods:

• Transcriptomic analysis to identify SEMA6D's regulatory functions.
• In vitro studies using RAW264.7 macrophages to evaluate SEMA6D overexpression effects on ASC, NLRP3, and M1 polarization.
• In vivo studies in an OA rat model (DMM) to assess SEMA6D's impact on synovial macrophage polarization and inflammatory mediators (IL-1β, IL-6).

Main Results:

• SEMA6D overexpression downregulated ASC and NLRP3, inhibiting M1 macrophage polarization.
• SEMA6D significantly reduced iNOS and IL-6 expression by over twofold.
• In vivo, SEMA6D overexpression decreased synovial M1 polarization, lowering IL-1β and IL-6 levels and mitigating cartilage degeneration.

Conclusions:

• SEMA6D demonstrates a protective effect in osteoarthritis.
• SEMA6D attenuates synovial macrophage-driven inflammation by inhibiting NLRP3 inflammasome activation.
• SEMA6D may serve as a novel therapeutic target for osteoarthritis by modulating macrophage polarization and inflammation.