Polyene Phosphatidylcholine Interacting with TLR-2 Prevents the Synovial Inflammation via Inactivation of MAPK and
Zixuan Xu1,2,3, Wenting Hao1,4, Daxiang Xu1
1Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Tongshan Road 209, Jiangsu Province, 221004, China.
Abstract:
Rheumatoid arthritis (RA) is a chronic autoimmune joint disease that causes cartilage and bone damage or even disability, seriously endangering human health. Chronic synovial inflammation has been shown to play a vital role in disease sustainability. Therefore, downregulation of synovial inflammation is considered to be an effective discipline for RA therapy. Polyene phosphatidylcholine (PPC) is a hepatoprotective agent, which was observed to inhibit inflammation in macrophages and prevent collagen-induced arthritis (CIA) of rats in our previous study. However, the underlying mechanism remains unclear. The present study further reported that PPC can inhibit synovial inflammation. In lipopolysaccharide (LPS)-stimulated primary synovial fibroblasts (SFs) of mice, PPC significantly decreased pro-inflammatory cytokines production while increasing anti-inflammatory cytokines level. In this process, PPC downregulated the expression of TLR-2 and their downstream signaling molecules such as MyD88, p-ERK1/2, p-JNK1/2, and p-P38 in MAPK pathway and p-IκBα and NF-κB-p65 in NF-κB pathway. Moreover, the inhibitory effect of PPC on the above molecules and cytokines was weakened after pre-treatment with TLR-2 agonist Pam3CSK4. In addition, PPC lost its anti-inflammatory effect and its suppressing capability on MAPK and NF-κB pathways in TLR-2-/- primary SFs after exposure to LPS. Collectively, this study demonstrated that PPC can alleviate synovial inflammation through TLR-2-mediated MAPK and NF-κB pathways, which can be proposed to be a potential drug candidate for RA prevention.
Insights
Polyene phosphatidylcholine (PPC) reduces synovial inflammation in rheumatoid arthritis (RA) by targeting the TLR-2 pathway. This study reveals PPC
Area of Science:
- Immunology
- Rheumatology
- Pharmacology
Background:
- Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation, leading to joint damage and disability.
- Chronic synovial inflammation is a key factor in RA pathogenesis, making its downregulation a therapeutic target.
- Polyene phosphatidylcholine (PPC), a known hepatoprotective agent, has previously shown anti-inflammatory effects and efficacy in preventing collagen-induced arthritis in rats, but its mechanism was unclear.
Purpose of the Study:
- To elucidate the mechanism by which Polyene phosphatidylcholine (PPC) inhibits synovial inflammation in the context of rheumatoid arthritis (RA).
- To investigate the role of Toll-like receptor 2 (TLR-2) and associated signaling pathways in PPC's anti-inflammatory effects on synovial fibroblasts.
Main Methods:
- Primary mouse synovial fibroblasts (SFs) were stimulated with lipopolysaccharide (LPS).
- The effects of PPC on pro-inflammatory and anti-inflammatory cytokine production were assessed.
- Expression levels of TLR-2, MyD88, MAPK pathway components (ERK1/2, JNK1/2, P38), and NF-κB pathway components (IκBα, NF-κB-p65) were analyzed.
- Experiments involved pre-treatment with a TLR-2 agonist (Pam3CSK4) and the use of TLR-2 knockout (TLR-2-/-) SFs.
Main Results:
- PPC significantly decreased pro-inflammatory cytokine production and increased anti-inflammatory cytokine levels in LPS-stimulated SFs.
- PPC downregulated the expression of TLR-2 and downstream signaling molecules in the MAPK and NF-κB pathways.
- The anti-inflammatory effects of PPC were diminished upon pre-treatment with a TLR-2 agonist and were absent in TLR-2-/- SFs.
Conclusions:
- Polyene phosphatidylcholine (PPC) alleviates synovial inflammation in rheumatoid arthritis (RA) by modulating the TLR-2-mediated MAPK and NF-κB signaling pathways.
- These findings suggest that PPC could be a potential therapeutic candidate for RA prevention.
- Targeting the TLR-2 pathway offers a promising strategy for managing RA-associated inflammation.
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