PI3K/Akt Signaling as a Potential Therapeutic Target for Reducing Inflammation and Corneal Stromal Injury in
Yuan Wei1, Xizhan Xu1, Yan Peng1
1Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, China.
Purpose:
This study aimed to investigate the role of the PI3K/Akt pathway in microsporidial stromal keratitis (MSK) and evaluate whether targeted inhibition of this pathway could provide a potential therapeutic strategy.
Methods:
A mouse model of MSK was established, followed by transcriptomic analysis to identify gene-expression changes following microsporidial infection. The activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway was assessed through real-time quantitative polymerase chain reaction (RT-qPCR), immunostaining, and protein phosphorylation assays. To explore therapeutic implications, the PI3K/Akt inhibitor LY294002 was administered by subconjunctival injection, and its effects on corneal inflammation and cytokine production were assessed over the course of infection.
Results:
Microsporidial infection markedly activated the PI3K/Akt pathway in the cornea, as evidenced by increased phosphorylation of PI3K and Akt. Transcriptomic analysis revealed upregulation of inflammatory cytokines, including MMP9, IL-1β, and TNF-α, indicating activation of inflammation-related pathways. Histologic analysis further confirmed increased immune cell infiltration and stromal edema in infected corneas. Pretreatment with LY294002 prior to infection alleviated the clinical manifestations of MSK, including corneal opacity, and reduced corneal expression of inflammatory expression levels, suggesting a contributory role of PI3K/Akt pathway in the pathogenesis and inflammation of MSK.
Conclusions:
PI3K/Akt signaling is a critical driver of inflammation in MSK. Targeting this pathway may present a promising strategy for the management of MSK. Future studies should focus on developing ocular-optimized inhibitors of the PI3K/Akt pathway and evaluating their safety and efficacy for potential clinical application in MSK treatment.
Insights
Targeting the PI3K/Akt pathway, crucial for inflammation in microsporidial stromal keratitis (MSK), offers a promising therapeutic strategy. Inhibiting this pathway reduced corneal inflammation and opacity in a mouse model of MSK.
Area of Science:
- Ophthalmology
- Immunology
- Molecular Biology
Background:
- Microsporidial stromal keratitis (MSK) is an inflammatory eye condition.
- The role of the PI3K/Akt pathway in MSK pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the involvement of the PI3K/Akt pathway in MSK.
- To evaluate the therapeutic potential of inhibiting the PI3K/Akt pathway in MSK.
Main Methods:
- Established a mouse model of MSK.
- Utilized transcriptomic analysis, RT-qPCR, immunostaining, and protein phosphorylation assays to assess PI3K/Akt pathway activation.
- Administered the PI3K/Akt inhibitor LY294002 to evaluate its therapeutic effects on corneal inflammation and cytokine production.
Main Results:
- Microsporidial infection activated the PI3K/Akt pathway in the cornea, indicated by increased PI3K and Akt phosphorylation.
- Transcriptomic analysis revealed upregulation of inflammatory cytokines (MMP9, IL-1β, TNF-α).
- LY294002 treatment alleviated MSK clinical signs, reduced corneal opacity, and decreased inflammatory markers.
Conclusions:
- The PI3K/Akt signaling pathway plays a critical role in driving inflammation in MSK.
- Targeting the PI3K/Akt pathway presents a potential therapeutic strategy for managing MSK.
- Further research is needed to develop and test ocular-specific PI3K/Akt inhibitors for clinical application in MSK treatment.
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