Investigative ophthalmology & visual science · 2022
Corneal Epithelium-Derived Netrin-1 Alleviates Dry Eye Disease via Regulating Dendritic Cell Activation.
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Yu Chaoqun, Chen Peng, Xu Jing, Wei Susu, Cao Qilong, Guo Chuanlong, Wu Xianggen, Di Guohu
Аннотация
PURPOSE: To investigate the expression of corneal epithelium-derived netrin-1 (NTN-1) and its immunoregulatory function in dry eye disease (DED) using a DED mouse model.
METHODS: We generated DED mouse models with desiccating stress under scopolamine treatment. RNA sequencing was performed to identify differentially expressed genes (DEGs) in the corneal epithelium of DED mice. NTN-1 expression was analyzed via real-time PCR, immunofluorescence staining, and immunoblotting. The DED mice were then treated with recombinant NTN-1 or neutralizing antibodies to investigate the severity of the disease, dendritic cell (DC) activation, and inflammatory cytokine expression.
RESULTS: A total of 347 DEGs (292 upregulated and 55 downregulated) were identified in the corneal epithelium of DED mice: corneal epithelium-derived NTN-1 expression was significantly decreased in DED mice compared to that in control mice. Topical recombinant NTN-1 application alleviated the severity of the disease, accompanied by restoration of tear secretion and goblet cell density. In addition, NTN-1 decreased the number of DCs, inhibited the activation of the DCs and Th17 cells, and reduced the expression of inflammatory factors in DED mice. In contrast, blocking endogenous NTN-1 activity with an anti-NTN-1 antibody aggravated the disease, enhanced DC activation, and upregulated the inflammatory factors in the conjunctivae of DED mice.
CONCLUSIONS: We identified decreased NTN-1 expression in the corneal epithelium of DED mice. Our findings elucidate the role of NTN-1 in alleviating DED and impeding DC activation, thereby indicating its therapeutic potential in suppressing ocular inflammation in DED.
METHODS: We generated DED mouse models with desiccating stress under scopolamine treatment. RNA sequencing was performed to identify differentially expressed genes (DEGs) in the corneal epithelium of DED mice. NTN-1 expression was analyzed via real-time PCR, immunofluorescence staining, and immunoblotting. The DED mice were then treated with recombinant NTN-1 or neutralizing antibodies to investigate the severity of the disease, dendritic cell (DC) activation, and inflammatory cytokine expression.
RESULTS: A total of 347 DEGs (292 upregulated and 55 downregulated) were identified in the corneal epithelium of DED mice: corneal epithelium-derived NTN-1 expression was significantly decreased in DED mice compared to that in control mice. Topical recombinant NTN-1 application alleviated the severity of the disease, accompanied by restoration of tear secretion and goblet cell density. In addition, NTN-1 decreased the number of DCs, inhibited the activation of the DCs and Th17 cells, and reduced the expression of inflammatory factors in DED mice. In contrast, blocking endogenous NTN-1 activity with an anti-NTN-1 antibody aggravated the disease, enhanced DC activation, and upregulated the inflammatory factors in the conjunctivae of DED mice.
CONCLUSIONS: We identified decreased NTN-1 expression in the corneal epithelium of DED mice. Our findings elucidate the role of NTN-1 in alleviating DED and impeding DC activation, thereby indicating its therapeutic potential in suppressing ocular inflammation in DED.