Melatonin Ameliorates Circadian Disruption‐Associated Dry Eye via Modulation of BMAL1‐REV‐ERBα‐IL‐17 Axis and Ocular Surface Microbiota Homeostasis

🥉 Top 5% JournalSep 12, 2025Journal of pineal research

Melatonin improves dry eye caused by disrupted daily rhythms by adjusting a key molecular clock pathway and maintaining healthy eye surface bacteria

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Mice exposed to chronic jet lag showed upregulated pro-inflammatory mediators associated with dry eye disease.

Chronic jet lag exposure led to conjunctival clock gene dysregulation.
Increased levels of pro-inflammatory mediators TNF-α, IL-6, and IL-17 were observed.
Transcriptomic analysis indicated significant activation of IL-17-mediated inflammatory pathways in conjunctival tissue.
Therapeutic neutralization of IL-17 reduced ocular surface inflammation and improved corneal epithelial integrity.
Melatonin treatment suppressed IL-17 expression and restored a balanced ocular surface microbiota.
Circadian disruption may influence ocular surface inflammation through the BMAL1-REV-ERBα-IL-17 signaling pathway.

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The association between modern lifestyle factors and dry eye disease (DED) pathogenesis has garnered increasing scientific attention. Emerging evidence implicates circadian disruption-a prevalent consequence of contemporary living patterns-as a significant yet not fully clarified pathogenic factor in DED development. To address this knowledge gap, we developed a circadian disruption mouse model using chronic jet lag exposure. Mice subjected to chronic jet lag exhibited conjunctival clock gene dysregulation and upregulated pro-inflammatory mediators, such as TNF-α, IL-6, and IL-17. Transcriptomic profiling demonstrated marked activation of IL-17-mediated inflammatory pathways within the conjunctival tissue. Therapeutic IL-17 neutralization substantially attenuated ocular surface inflammation, improved corneal epithelial integrity, and decreased apoptotic cell density in circadian disruption-induced dry eye mouse model. Moreover, REV-ERBα agonism potently suppressed IL-17 transcription, whereas BMAL1 deficiency exacerbated IL-17-driven inflammatory responses through REV-ERBα downregulation. Chronic jet lag additionally induced ocular surface microbiota dysbiosis, characterized by Firmicutes overproliferation. Melatonin administration effectively suppressed conjunctival IL-17 expression through BMAL1-REV-ERBα pathway activation while reducing the relative abundance of Firmicutes to restore ocular surface microbiota balance. Our study reveals that circadian disruption induces ocular surface inflammation through the BMAL1-REV-ERBα-IL-17 signaling axis and exacerbates dysbiosis of the ocular surface microbiota. Melatonin mitigates these pathological alterations via dual-directional modulation of circadian-immune signaling crosstalk and restoration of microbiota balance. Importantly, this study establishes melatonin as a multifaceted therapeutic agent for combating lifestyle-associated DED, while elucidating the underlying mechanisms governing circadian rhythm-microbiome axis dynamics in ocular surface pathogenesis.

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