Histone deacetylase inhibitor attenuates experimental fungal keratitis in mice

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.

Deep learning-based automated diagnosis of fungal keratitis with in vivo confocal microscopy images

“…Fungal keratitis (FK) is a serious corneal infection caused by fungal organisms and is the main cause of vision loss and blindness, especially in developing countries (1,2). Early diagnosis and treatment are the key to preventing severe complications, such as corneal perforation, anterior chamber empyema, endophthalmitis and blindness (3)(4)(5).…”

Isorhamnetin Ameliorates Aspergillus fumigatus Keratitis by Reducing Fungal Load, Inhibiting Pattern-Recognition Receptors and Inflammatory Cytokines

“…29,57 Interestingly, the fungal load could be reduced exclusively through inhibiting inflammatory response. 58,59 For instance, blocking inflammation with suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, could reduce fungal burden in FK mice, 59 but the underlying mechanism needs to be further studied.…”

Experimental Models for Fungal Keratitis: An Overview of Principles and Protocols

“…at 24 and 48 h following a scratch-and-toothpick inoculation with F. solani hyphal fragments (inoculum size not quantitated). The treatment resulted in a decreased disease severity that was associated with a downregulation of TLR-4, TNFα, and IL-1β compared to untreated controls [45].…”

“…One such experimental workflow in this regard is as follows: a 2 mm diameter trephine is used to mark the central cornea, and then a size-11 scalpel blade is used to cut into the epithelium within the marked area. Then, a sharpened bamboo toothpick is used to debride and smear F. solani mycelium onto the ocular surface [ 42 , 43 , 44 , 45 , 46 ]. Such a method can also be used for A. fumigatus as demonstrated in Figure 2 B (unpublished data).…”