Inhibition of P2X4 suppresses joint inflammation and damage in collagen-induced arthritis
Faxin Li1, Nongjian Guo, Yuxia Ma
1Department of Rheumatology, Jinan Central Hospital Affiliated to Shandong University, Jinan, 250013, Shandong, China.
Abstract:
Recent data have shown that the purinergic receptor P2X4 plays key roles in inflammatory responses. We evaluated whether P2X4 inhibition could affect the development of arthritis and autoimmunity in collagen-induced arthritis (CIA) model. P2X4 antisense oligonucleotide (asODN) was injected intravenously via tail vein into the CIA mice to selectively inhibit P2X4 expression daily for 14 days. P2X4 asODN treatment reduced the clinical score of CIA in mice. P2X4 asODN also decreased the levels of serum IL-1β, TNF-α, IL-6, and IL-17. P2X4 asODN treatment significantly inhibited synovial inflammation and joint destruction. P2X4 asODN treatment also suppressed the NLR family, pyrin domain containing 1 (NLRP1) inflammasome activation in CIA mice and synovial cells of human rheumatoid arthritis. These data show that P2X4 asODN confers a therapeutic benefit on CIA. Inhibition of the NLRP1 inflammasome signaling pathway is the underlying mechanism of action.
Insights
Inhibiting the P2X4 receptor with antisense oligonucleotide (asODN) reduced arthritis symptoms and joint destruction in a collagen-induced arthritis (CIA) mouse model. This therapeutic benefit is linked to suppressing NLRP1 inflammasome activation.
Area of Science:
- Immunology
- Rheumatology
- Molecular Biology
Background:
- The purinergic receptor P2X4 is implicated in inflammatory processes.
- Collagen-induced arthritis (CIA) is a common model for studying rheumatoid arthritis and autoimmune diseases.
Purpose of the Study:
- To investigate the therapeutic potential of P2X4 inhibition in the CIA model.
- To elucidate the role of P2X4 in arthritis development and autoimmunity.
Main Methods:
- Mice with CIA were treated with P2X4 antisense oligonucleotide (asODN) administered intravenously daily for 14 days.
- Clinical scores, serum cytokine levels (IL-1β, TNF-α, IL-6, IL-17), synovial inflammation, joint destruction, and NLRP1 inflammasome activation were assessed.
Main Results:
- P2X4 asODN treatment significantly reduced clinical scores in CIA mice.
- Serum levels of pro-inflammatory cytokines IL-1β, TNF-α, IL-6, and IL-17 were decreased by P2X4 asODN.
- Synovial inflammation, joint destruction, and NLRP1 inflammasome activation were significantly inhibited in CIA mice and human rheumatoid arthritis synovial cells.
Conclusions:
- P2X4 asODN demonstrates therapeutic efficacy in the CIA model of arthritis.
- The mechanism of action involves the suppression of the NLRP1 inflammasome signaling pathway.
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