Abstract
Purpose: To explore whether 5-HT1A receptors are involved in the dry eye disease (DED) mouse model and reveal its underlying mechanism.Methods: A C57BL/6J mouse DED model was established via the administration of 0.2% benzalkonium chloride twice a day for 14 days. Corneal fluorescein sodium staining score and Schirmer I test were checked before, and on days 7, 14, and 21 after treatment. The experiment was randomly divided into control, DED, 5-HT1A receptor agonist with or without N-acetylcysteine (NAC) and 5-HT1A receptor antagonist with or without NAC groups. The mRNA expression of inflammatory cytokines was measured by reverse transcription-quantitative polymerase chain reaction. Cellular reactive oxygen species (ROS) were detected by 2', 7'-dichlorodihydrofluorescein diacetate assays. Western blot analysis was used to measure the expression levels of autophagic proteins microtubule-associated protein 1 light chain 3 (LC3B-I/II) and autophagy-related gene 5 (ATG5).Results: 5-HT1A receptor agonist (8-OH-DPAT) increased corneal fluorescein sodium staining spots and 5-HT1A receptor antagonist (WAY-100635) decreased them. Treatment with 8-OH-DPAT was associated with the gene expression of more inflammatory cytokines, such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), C-C motif chemokine ligand 2 (CCL2) and C-X-C motif chemokine ligand 10 (CXCL10) compared with treatment with WAY-100635. An increased expression of LC3B-I/II and ATG5 was observed in corneal epithelial cells in the mouse model of DED. 8-OH-DPAT significantly enhanced the expression of LC3B-I/II and ATG5 by disrupting ROS levels. WAY-100635 alleviates autophagy by inhibiting ROS production.Conclusion: Excessive ROS release through 8-OH-DPAT induction can lead to impaired autophagy and increased inflammatory response in DED. WAY-100635 reduces corneal epithelial defects and inflammation in DED, as well as alleviates autophagy by inhibiting ROS production. The activation of the 5-HT1A receptor-ROS-autophagy axis is critically involved in DED development.
Highlights
Dry eye disease (DED) is a chronic and multifactorial ocular surface disease that affects 5–35% of the worldwide population, with its prevalence increasing with age [1]
The staining scores of corneal fluorescein were higher in 8-OH-DPAT-treated mice (11.23 ± 0.84) than in WAY-100635-treated mice (6.8 ± 0.75, P < 0.01) and mice in the DED groups (9.89 ± 0.71, P < 0.05) (Figure 1E)
No differences in tear secretion were observed among the DED, 8-OH-DPAT and WAY-100635 groups (Figures 1F,G). 8-OHDPAT treatment induced a typical corneal epithelial defect and WAY-100635 reduced corneal epithelial injury
Summary
Dry eye disease (DED) is a chronic and multifactorial ocular surface disease that affects 5–35% of the worldwide population, with its prevalence increasing with age [1]. Patients with DED suffer from ocular discomfort, which affects their vision-related quality of life [2]. Increased tear film hyperosmolarity and instability lead to the damage of the corneal epithelium through a cascade of inflammatory events, inducing neurosensory abnormalities [2, 3]. The treatment of depression with selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors induces the secretion of proinflammatory cytokines, and cell apoptosis on the ocular surface aggravates depression-associated DED by activating the nuclear factor-κB (NF-κB) pathway [4]. The 5-HT1A receptor gene is a strong candidate for the treatment of depression, as it has been shown to inhibit depression symptoms in 5-HT1A receptor knockout mouse models [7,8,9]
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