Sirt6 deficiency impairs corneal epithelial wound healing

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.

<p>Sirt6-Mediated Endothelial-to-Mesenchymal Transition Contributes Toward Diabetic Cardiomyopathy via the Notch1 Signaling Pathway</p>

“…28 In addition, the Sirt6 and Notch signaling pathways have been reported to regulate podocyte injury and proteinuria, 29 whereas Sirt6 deficiency was found to impact corneal epithelial wound healing via Notch signaling. 30 Consistently, our study demonstrated that Sirt6 deficiency contributes toward EndMT induced by HG+PA via Notch1 signaling.…”

dsRNA Induced IFNβ-MMP13 Axis Drives Corneal Wound Healing

“…Corneal injury may result in susceptibility scarring, opacification, and loss of visual acuity. 6 , 35 Proper wound repair is vital for corneal epithelial integrity and transparency. 36 , 37 Our work provides new insights into the corneal wound healing process and identifies the IFNβ-MMP13 axis as a potential therapeutic target to promote corneal regeneration.…”

Myeloid cell-specific sirtuin 6 deficiency delays wound healing in mice by modulating inflammation and macrophage phenotypes

“…Similarly, the sirtuin activator resveratrol accelerates wound repair by increasing keratinocyte proliferation, while the sirtuin inhibitor sirtinol retards wound closure 27 . More recently, Hu et al 28 showed that Sirt6 KO mice display delayed and incomplete healing of the cornea after wounding. These reports suggest a beneficial role for sirtuin (specifically Sirt6) activation in wound healing.…”