Abstract
Corneal transparency, dependent on the integrity of epithelial cells, is essential for vision. Corneal epithelial damage is one of the most commonly observed ocular conditions and proper wound healing is necessary for corneal transparency. Sirt6, a histone deacetylase, has been shown to regulate many cellular events including aging and inflammation. However, its specific role in corneal epithelial wound healing remains unknown. Here we demonstrated that Sirt6 was expressed in corneal epithelial cells and its expression decreased with age. In an in vivo corneal epithelial wound healing model, Sirt6 deficiency resulted in delayed and incomplete wound healing and was associated excessive inflammation in the corneal stroma and dysfunction of Notch signaling, leading to keratinization of the corneal epithelium and corneal opacity. Aging Sirt6-deficient mice spontaneously developed corneal keratitis with extensive infiltration of inflammatory cells into the cornea. In vitro experiments demonstrated that primary corneal epithelial cells with Sirt6 downregulation expressed increased basal levels of inflammatory genes and exhibited hyper-inflammatory reactivity to IL-1β and TNFα treatment. These results provide compelling evidence that Sirt6 is a critical regulator of inflammation in the cornea, and is responsible for corneal epithelial wound healing, thus contributing to the maintenance of epithelial integrity and corneal transparency.
Highlights
The cornea, an avascular and transparent tissue of the eye, is composed of four main layers: an outer epithelial layer, a middle stromal layer, a Descemet's membrane and an inner layer of endothelial cells [1,2,3]
We found Sirt6 was expressed in corneal extract from wild type (WT) mice (Fig. 1A) and www.aging-us.com its immunoreactivity was highest in corneal epithelium other cells including stromal keratocytes and endothelial cells are positive for Sirt6 staining (Fig. 1B)
Our results suggest that Sirt6 is functionally expressed in the mouse cornea and its expression decreases with age
Summary
The cornea, an avascular and transparent tissue of the eye, is composed of four main layers: an outer epithelial layer, a middle stromal layer, a Descemet's membrane and an inner layer of endothelial cells [1,2,3]. The primary function of corneal epithelium is to serve as a protective barrier against physical trauma, pathogens and chemicals, and its structural integrity is essential for the transparency of the cornea and good vision [3, 4]. Once epithelium is altered by disease or trauma, it can result in chronic inflammation, keratolysis, deposition of irregular collagen, and further damage to the underlying basement membrane and stroma. Normal epithelial wound healing is essential to maintain the structure and function of the cornea [4].
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