Investigative ophthalmology & visual science · 2025
Cyclosporine A Ameliorates Inflammatory Responses in Dry Eye by Inactivating cGAS-STING Signaling Via the Initiation of Autophagy.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Han Xinyang, Zhang Jingyi, Chen Chen, Zhang Sai, Zhao Xinmei, Wang Ruoqing, Sun Xia, Jiang Pengfei, Li Yuanbin
Аннотация
PURPOSE: The purpose of this research was to examine the roles and regulatory mechanisms of autophagy and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway in dry eye (DE) inflammation and the mechanism by which cyclosporine A (CsA) attenuates the inflammatory response in dry eye disease (DED) by modulating autophagy and the cGAS-STING pathway.
METHODS: Two DE models, hypertonicity-stimulated human corneal epithelial (HCE-T) cells and benzalkonium chloride (BAC)-treated C57BL/6 mice, were established to investigate the modulation of autophagy and the cGAS-STING pathway by CsA in DE. Changes in light chain 3 (LC3), P62, γ-H2AX, cGAS, and STING levels were detected via western blotting. Reverse-transcription quantitative PCR was used to detect changes in IL-6 and IL-1β mRNA levels after drug administration, and autophagosomes were observed via electron microscopy. The autophagy inhibitor 3-methyladenine (3-MA) was used to further clarify the effects of autophagy on the cGAS-STING pathway. Hematoxylin and eosin staining and corneal fluorescence staining were used to assess the signs of DE in the mice.
RESULTS: Autophagy and the cGAS-STING pathway were significantly activated in hypertonicity-stimulated HCE-T cells and in the BAC-induced DE model. CsA activated autophagy and decreased the levels of γ-H2AX, cGAS, STING, IL-6, and IL-1β in the DE models. The autophagy inhibitor 3-MA reversed the inhibitory effects of CsA on the cGAS-STING pathway and the inflammatory response. Similarly, in vivo experiments revealed that CsA activated autophagy, inhibited the expression of components of the cGAS-STING pathway, promoted the restoration of corneal epithelial cell morphology, and reduced corneal fluorescence staining scores in mice with DE.
CONCLUSIONS: CsA inhibited the cGAS-STING pathway by activating autophagy, further reducing inflammation in DE models and attenuating the signs of DE in mice.
METHODS: Two DE models, hypertonicity-stimulated human corneal epithelial (HCE-T) cells and benzalkonium chloride (BAC)-treated C57BL/6 mice, were established to investigate the modulation of autophagy and the cGAS-STING pathway by CsA in DE. Changes in light chain 3 (LC3), P62, γ-H2AX, cGAS, and STING levels were detected via western blotting. Reverse-transcription quantitative PCR was used to detect changes in IL-6 and IL-1β mRNA levels after drug administration, and autophagosomes were observed via electron microscopy. The autophagy inhibitor 3-methyladenine (3-MA) was used to further clarify the effects of autophagy on the cGAS-STING pathway. Hematoxylin and eosin staining and corneal fluorescence staining were used to assess the signs of DE in the mice.
RESULTS: Autophagy and the cGAS-STING pathway were significantly activated in hypertonicity-stimulated HCE-T cells and in the BAC-induced DE model. CsA activated autophagy and decreased the levels of γ-H2AX, cGAS, STING, IL-6, and IL-1β in the DE models. The autophagy inhibitor 3-MA reversed the inhibitory effects of CsA on the cGAS-STING pathway and the inflammatory response. Similarly, in vivo experiments revealed that CsA activated autophagy, inhibited the expression of components of the cGAS-STING pathway, promoted the restoration of corneal epithelial cell morphology, and reduced corneal fluorescence staining scores in mice with DE.
CONCLUSIONS: CsA inhibited the cGAS-STING pathway by activating autophagy, further reducing inflammation in DE models and attenuating the signs of DE in mice.
Предметные рубрики MeSH
AnimalsAutophagyDry Eye SyndromesNucleotidyltransferasesMembrane ProteinsSignal TransductionCyclosporineMiceMice, Inbred C57BLHumansDisease Models, AnimalBlotting, WesternEpithelium, CornealImmunosuppressive AgentsCells, CulturedMaleInflammationSTING ProteinCyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase