Celastrol ameliorates Aspergillus fumigatus keratitis via inhibiting LOX-1

Area of Science:

• Ophthalmology
• Immunology
• Pharmacology

Background:

• Fungal keratitis, particularly Aspergillus fumigatus keratitis, poses a significant threat to vision.
• Current treatments for fungal keratitis can have limitations, necessitating the exploration of novel therapeutic agents.
• Celastrol (CLT) is a natural compound with known anti-inflammatory properties.

Purpose of the Study:

• To evaluate the therapeutic potential of Celastrol (CLT) in a mouse model of Aspergillus fumigatus (A. fumigatus) keratitis.
• To investigate the underlying mechanisms of CLT's action, focusing on inflammatory mediators and Lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1).

Main Methods:

• Primary peritoneal macrophages from C57BL/6 mice were pretreated with CLT before stimulation with A. fumigatus hyphae.
• C57BL/6 mice were infected with A. fumigatus, and corneas were treated with CLT post-infection.
• Clinical scores, PCR, ELISA, and Western blot analyses were performed to assess inflammatory mediators (IL-1β, TNF-α, IL-10, TGF-β, MIP-2), LOX-1 expression, and p38MAPK phosphorylation.

Main Results:

• CLT treatment significantly reduced disease severity in A. fumigatus keratitis.
• CLT markedly inhibited the mRNA and protein levels of pro-inflammatory and anti-inflammatory mediators, including IL-1β, TNF-α, IL-10, TGF-β, MIP-2, and LOX-1.
• CLT pretreatment significantly inhibited p38MAPK phosphorylation in macrophages stimulated with A. fumigatus.

Conclusions:

• Celastrol (CLT) effectively ameliorates Aspergillus fumigatus keratitis in a mouse model.
• CLT exerts its therapeutic effect by inhibiting LOX-1 expression.
• CLT's anti-inflammatory action in macrophages may be mediated through the p38MAPK signaling pathway.