A mouse model of meibomian gland hyperkeratinization-induced dry eye

Meibomian glands (MGs) in the eyelid secrete lipids that stabilize the tear film and protect the ocular surface. Abnormal MGs are associated with dry eye disease (DED), one of the most common ophthalmological disorders, but the molecular alterations underlying DED remain unclear. For most patients, DED is thought to be caused by the failure of MG-derived lipids to exit the gland due to hyperkeratinization-induced ductal obstruction; however, this theory has been difficult to test due to a lack of mouse models that recapitulate this phenotype. Here, we show that the MG central duct is lined by terminally differentiated cells that express Keratin 6, Keratin 79 and Abca12, a lipid transporter that promotes desquamation in the skin. Targeted genetic disruption of Abca12 in Keratin 6+ ductal cells causes a transient dry eye phenotype that is associated with severe hyperkeratosis and lipid retention specifically in the MG central duct. These findings demonstrate that constant desquamation is required to prevent MG ductal obstruction, and suggest that factors that modulate DED pathogenesis, including age, environment, inflammation and behavior, may converge on Abca12.