TLR8 aggravates skin inflammation and fibrosis by activating skin fibroblasts in systemic sclerosis

Objectives: Innate immunity significantly contributes to systemic sclerosis (SSc) pathogenesis. TLR8 is an important innate immune mediator that is implicated in autoimmunity and fibrosis. However, the expression, mechanism of action, and pathogenic role of TLR8 in SSc remain unclear. The aim of this study was to explore the roles and underlying mechanisms of TLR8 in SSc.

Methods: The expression of TLR8 was analyzed based on a public dataset and then verified in skin tissues and skin fibroblasts of SSc patients. The role of TLR8 in inflammation and fibrosis was investigated using a TLR8-overexpression vector, activator (VTX-2337), inhibitor (cu-cpt-8m), and TLR8 siRNA in skin fibroblasts. The pathogenic role of TLR8 in skin inflammation and fibrosis was further validated in a bleomycin (BLM)-induced mouse skin inflammation and fibrosis model.

Results: TLR8 levels were significantly elevated in SSc skin tissues and myofibroblasts, along with significant activation of the TLR8 pathway. In vitro studies showed that overexpression or activation of TLR8 by a recombinant plasmid or VTX-2337 upregulated IL-6, IL-1β, COL I, COL III, and α-SMA in skin fibroblasts. Consistently, both TLR8-siRNA and cu-cpt-8m reversed the phenotypes observed in TLR8-activating fibroblasts. Mechanistically, TLR8 induces skin fibrosis and inflammation in a manner dependent on the MAPK, NF-κB, and SMAD2/3 pathways. Subcutaneous injection of cu-cpt-8m significantly alleviated BLM-induced skin inflammation and fibrosis in vivo.

Conclusion: TLR8 might be a promising therapeutic target to improve the treatment strategy for SSc skin inflammation and fibrosis.

 

Comments:

This study aimed to investigate the role of Toll-like receptor 8 (TLR8) in systemic sclerosis (SSc), focusing on its expression, mechanism of action, and pathogenic role. Here's a breakdown of the key findings and conclusions:

1. **Elevated TLR8 Expression in SSc:** The study began by analyzing a public dataset and confirmed that TLR8 expression is significantly increased in both skin tissues and skin fibroblasts of SSc patients. This suggests that TLR8 may be involved in the pathogenesis of SSc.

2. **Activation of TLR8 Pathway:** Along with elevated TLR8 expression, the study observed significant activation of the TLR8 pathway in SSc skin tissues and myofibroblasts, indicating its potential involvement in the disease.

3. **Role of TLR8 in Inflammation and Fibrosis:** In vitro experiments demonstrated that overexpression or activation of TLR8 in skin fibroblasts led to upregulation of pro-inflammatory cytokines (IL-6 and IL-1β) as well as fibrosis-associated markers (COL I, COL III, and α-SMA). Conversely, the inhibition of TLR8 using TLR8 siRNA or cu-cpt-8m reversed these phenotypic changes, suggesting that TLR8 plays a role in promoting inflammation and fibrosis in SSc.

4. **Underlying Mechanisms:** Mechanistically, the study found that TLR8-induced skin fibrosis and inflammation were dependent on several signaling pathways, including MAPK, NF-κB, and SMAD2/3.

5. **In Vivo Validation:** To validate the pathogenic role of TLR8 in SSc, the researchers used a bleomycin-induced mouse model of skin inflammation and fibrosis. Subcutaneous injection of cu-cpt-8m, a TLR8 inhibitor, significantly alleviated the skin inflammation and fibrosis induced by bleomycin in the mouse model.

6. **Conclusion:** The study concludes that TLR8 may be a promising therapeutic target for improving the treatment strategy for SSc-related skin inflammation and fibrosis. Inhibiting TLR8 using compounds like cu-cpt-8m could potentially mitigate these pathological processes.

Overall, this research provides valuable insights into the role of TLR8 in SSc and suggests that further investigations into TLR8-targeted therapies may hold promise for managing this autoimmune disease.

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