Abstract
Fungal keratitis is one of the leading causes of blindness of infected corneal diseases, but the pathogenesis of fungal keratitis is not fully understood and therefore the treatment of the disease by medication is still under investigation. In the current study, we sought to study the effect of HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) on experimental fungal keratitis in mice. SAHA (25 mg/kg) (n = 30) or vehicle (DMSO) (n = 30) was delivered through intraperitoneal injection (IP) 24 hours after the fungal inoculation, and the same amount of SAHA injection or DMSO was followed at day 2. The expression of histone H3 (H3), acetylated histone H3 (AC-H3), histone deacetylase 1 (HDAC)1, tumor necrosis factor-α (TNFα), and Toll-like receptor 4 (TLR4) in surgically excised specimens from the patients and mice with fungal keratitis were detected by immunohistochemistry. The expression of mRNAs for Interleukin-1β (IL-1β), TNFα, and TLR4 were evaluated in the corneas of the mice with fungal infection and the control corneas by real-time PCR. The quantification of IL-1β and TNFα in the corneas of the mice with fungal infection was determined by ELISA. The inhibitory effect of SAHA on mice fungal keratitis was revealed by GMS and H&E staining. We found that the downregulation of histone acetylation and upregulation of HDAC1 expression were associated with the increased inflammation response in fungal keratitis not only in humans but also in experimental animals. SAHA was able to inhibit experimental fungal keratitis in mouse by suppressing TLR4 and inflammatory cytokines such as TNFα and IL-1β; the inhibition of HDAC may be a potential therapeutic approach for the treatment of fungal keratitis.
Highlights
Fungal keratitis is one of the most prevalent corneal diseases and is a major contributor to vision loss and blindness, especially in the developing countries
We investigated the expression of histone H3 (H3), acetylated histone H3 (AC-H3), HDAC1, Toll-like receptor 4 (TLR4), tumor necrosis factor-α (TNFα), and IL-1β in corneal specimens from patients with fungal keratitis and mice with experimental fungal keratitis
Reduced acetylated histone H3 (AC-H3) expression and increased HDAC1 expression in the corneal sections of human fungal keratitis and experimental fungal keratitis in mice compared with control were demonstrated by immunohistochemistry
Summary
Fungal keratitis is one of the most prevalent corneal diseases and is a major contributor to vision loss and blindness, especially in the developing countries. Medications for anti-fungal infection have limited efficacy and drug-resistance rapidly develops, suggesting that fungal keratitis is a complex disease and other mechanisms may participate in the pathogenesis of the disease. In terms of the application of HDACi to suppress inflammation, suberoylanilide hydroxamic acid (SAHA) has shown great promise as an anti-inflammation agent[13,14,15] It exerts effects by targeting the major pre-inflammatory cytokines such as TNFα, IL-1β and TLR415,16, Of note, SAHA is approved by FDA for treatment of T-cell lymphoma[17]. Previous publications have suggested that HDACs play an important role in the pathogenesis of fungal infection, the relevance of histone acetylation and fungal keratitis, especially the effect of HDAC inhibitor on fungal keratitis, have not been studied. We observed the inhibitory effect of SAHA on mice fungal keratitis
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