Corneal Sensory Nerve Injury Disrupts Lacrimal Gland Function by Altering Circadian Rhythms in Mice

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Purpose: To investigate the impact of corneal sensory nerve injury on lacrimal gland function, focusing on mechanisms involving the superior salivatory nucleus (SSN), circadian rhythm disruption, immune microenvironment alterations, and the potential for neural regeneration. Methods: A murine model of corneal sensory nerve injury was used to assess lacrimal gland function, with tear secretion measured using the phenol red thread test. Transcriptomic analysis of lacrimal glands examined circadian rhythm and immune-related gene expression. Basic fibroblast growth factor (bFGF) was used to promote corneal nerve regeneration, and its effects on tear secretion and nerve repair were evaluated. Results: Corneal nerve injury resulted in a 35% reduction in tear secretion and significantly impaired SSN activity, as evidenced by a 31% decrease in c-FOS-positive neurons in choline acetyltransferase (ChAT)-expressing neurons. Transcriptomic analysis revealed significant downregulation of immune-related pathways, including Toll-like receptor (TLR), NOD-like receptor (NLR), and T-cell receptor signaling. Circadian rhythm gene expression exhibited phase shifts, with a 2.13-hour delay in peak expression and a substantial change in the number and types of rhythmic genes, which were enriched in different signaling pathways. The bFGF treatment restored tear secretion by 22% and promoted nerve regeneration, although nerve fiber density remained 74% lower than that of controls. Conclusions: Corneal sensory nerve injury disrupts both central and peripheral circadian clock functions in the lacrimal gland, leading to reduced tear secretion and immune dysregulation. These findings highlight the novel role of circadian rhythms and neural-immune interactions in lacrimal gland dysfunction. Neural regeneration strategies, such as bFGF, offer therapeutic potential for dry eye syndrome, providing new directions for clinical intervention.

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