Circadian disruption reduces MUC4 expression via clock molecule BMAL1 during dry eye development

Abstract Circadian disruption, as a result of shiftwork, jet lag and other lifestyle factors, is a common public health problem associated with a wide range of diseases, such as metabolic disorders, neurodegenerative diseases and cancer. In the present study, we established a chronic jet lag model using a time shift every 3 days method and assessed the effects of circadian disruption on the ocular surface homeostasis. Our results indicated that jet lag increased corneal epithelial defects, cell apoptosis, and proinflammatory cytokine expression. However, there was no significant change in the volume of tear secretion or conjunctiva goblet cells after 30 days for jet lag. At the same time, further analysis of the pathogenic mechanism using RNA sequencing prompted that jet lag caused corneal transmembrane mucin deficiency, specifically MUC4. The crucial role of MUC4 in the pathogenic progression was demonstrated by the protection of corneal epithelial cells and the inhibition of inflammation activation following MUC4 replenishment. Unexpectedly, the genetic ablation of BMAL1 in mice caused MUC4 deficiency and dry eye disease. The underlying mechanism was uncovered in cultured human corneal epithelial cells in vitro, where the silencing of BMAL1 reduced MUC4 and the overexpression of BMAL1 increased MUC4. Furthermore, melatonin, a circadian rhythm restorer, had a therapeutic effect for jet lag-induced dry eye by restoring the expression of BMAL1, which upregulated MUC4. These findings identify a novel dry eye mouse model induced by circadian disruption, shed light on the mechanism and provide a potential clinical treatment.