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Herbal compound cepharanthine attenuates inflammatory arthritis by blocking macrophage M1 polarization

Objective: Cepharanthine (CEP) is a drug candidate for tumor, viral infection, and some inflammatory diseases, but its effect on rheumatoid arthritis (RA) and the underlying mechanism are incompletely understood.

Methods: CEP was administered intraperitoneally to a collagen-induced arthritis (CIA) model. Joints went radiological and histological examination and serum cytokines were examined with cytometry-based analysis. M1 macrophages were induced from THP-1 cells or mouse bone marrow-derived macrophages with LPS and IFN-γ. Bulk RNA-seq was performed on macrophage undergoing M1-polarizatioin. Western blotting was applied to determine pathways involved in monocyte chemotaxis and polarization. Glycolysis metabolites were measured by chemiluminescence while glycolytic enzymes were examined by quantitative PCR.

Results: We found CEP significantly ameliorated synovial inflammation and joint destruction of CIA mice. It downregulated TNF-α levels in serum and in joints. The number of M1 macrophages were reduced in CEP-treated mice. In vitro, CEP inhibited monocyte chemotaxis to MCP-1 by downregulating CCR2 and reducing ERK1/2 signaling. Additionally, CEP suppressed M1 polarization of macrophages induced by LPS and IFN-γ. Genes involved in IFN-γ signaling, IL-6-JAK/STAT3 signaling, glycolysis, and oxidative phosphorylation process were downregulated by CEP. Several enzymes critically involved in glycolytic metabolism were suppressed by CEP, which resulted in reduced citrate in M1-polarizing macrophages. The inhibitory effect of CEP on macrophage polarization might be attributed to the blockage of TLRs-MyD88/IRAK4-IRF5 signaling pathway together with suppression of overactivated glycolytic metabolism in M1-polarizing macrophages.

Conclusion: CEP attenuated joint inflammation by suppressing monocyte chemotaxis and proinflammatory differentiation. It has the potential to be developed into a complementary or alternative therapy for RA.

 

Comments:

The study conducted on Cepharanthine (CEP) in a collagen-induced arthritis (CIA) model appears quite promising for rheumatoid arthritis (RA) treatment. The key findings suggest multiple positive impacts of CEP:

1. **Synovial Inflammation and Joint Destruction:** CEP significantly reduced synovial inflammation and joint destruction in CIA mice, indicating its potential as a treatment for RA.

2. **Downregulation of TNF-α:** CEP lowered TNF-α levels both in serum and joints, a crucial pro-inflammatory cytokine associated with RA.

3. **Reduction of M1 Macrophages:** CEP decreased the number of M1 macrophages, known for their pro-inflammatory characteristics, indicating a modulation of the immune response.

4. **Inhibition of Monocyte Chemotaxis and M1 Polarization:** CEP hindered monocyte chemotaxis to MCP-1 by downregulating CCR2 and suppressed M1 polarization of macrophages induced by LPS and IFN-γ.

5. **Modulation of Signaling Pathways and Metabolism:** CEP impacted various signaling pathways, including IFN-γ, IL-6-JAK/STAT3, and glycolysis. It also suppressed overactivated glycolytic metabolism in M1-polarizing macrophages.

6. **Targeted Pathways:** The study suggests that CEP might inhibit the TLRs-MyD88/IRAK4-IRF5 signaling pathway, contributing to the suppression of macrophage polarization.

The combination of inhibiting chemotaxis, suppressing M1 polarization, and modulating signaling pathways and metabolism demonstrates the potential efficacy of CEP in mitigating RA symptoms. This research offers valuable insights into the mechanisms underlying its therapeutic effects, potentially positioning CEP as a complementary or alternative therapy for RA. Further studies and clinical trials could validate its efficacy and safety for human use.

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TNF-alpha