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Long Non-coding RNAs Gabarapl2 and Chrnb2 Positively Regulate Inflammatory Signaling in a Mouse Model of Dry Eye.

ABSTRACT: Purpose: To elucidate the expression profile and the potential role of long non-coding ribonucleic acids (RNAs) (lncRNAs) in a dry eye disease (DED) model. Methods: A DED model was established in C57BL/6J mice with 0.2% benzalkonium chloride (BAC) twice a day for 14 days. The differentially expressed lncRNAs were detected by RNA-seq technology (Gene Expression Omnibus, GEO GSE186450) and the aberrantly expressed lncRNAs were further verified by RT-qPCR. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to predicate the related candidate genes and potential pathological pathways. Cells from a human corneal epithelial cell line (HCECs) were cultured under hyperosmolarity. The regulation of inflammatory factors by silencing potential targeted lncRNAs was verified in vitro in HCECs. Results: In our study, a significant increase in corneal fluorescence staining and a reduction in tear production were observed in DED mice at all follow-ups compared with the controls, and the differences were increasing over time. In total, 2,649 upregulated and 704 downregulated lncRNAs were identified in DED mice. We selected six aberrantly expressed and most abundant lncRNAs and performed RT-qPCR using the samples for RNA-seq. Chrnb2, Gabarapl2, and Usp31 were thereby confirmed as the most significantly altered lncRNAs. Pathway analysis revealed that the neuroactive ligand-receptor interaction signaling pathway was the most enriched, followed by the calcium signaling pathway and cytokine-cytokine receptor interaction. Following treatment of Gabarapl2 siRNA and Chrnb2 siRNA, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 were significantly downregulated in the HCECs. Conclusion: Our study suggests that Chrnb2 and Gabarapl2 may be involved in the inflammation response by regulating TNF-α, IL-1β, and IL-6 in DED. These candidate lncRNAs may be both potential biomarkers and therapeutic targets for DED.

SUBMITTER: Yang Y

PROVIDER: S-EPMC8703135 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo investigate the clinical effects of IRT5 probiotics in the environmental dry eye model.MethodsEight week old male C57BL/6 mice were randomly divided into two groups; control group (n = 16) received oral gavage of 300 μL phosphate-buffered saline (PBS) alone once daily, IRT5 group (n = 9) received oral gavage of 1 x 109 CFU IRT5 probiotics powder in 300 μL PBS once daily, both groups for 11 to 12 days. Simultaneously, all mice underwent dry eye induction. Tear secretion, corneal staining and conjunctival goblet cell density were evaluated. Quantative real-time polymerase chain reaction (RT-PCR) for inflammation-related markers was performed. 16S ribosomal RNA of fecal microbiome was analyzed and compositional difference, alpha and beta diversities were assessed.ResultsThere was no difference in NEI score but significant increase in tear secretion was observed in IRT5 group (p < 0.001). There was no significant difference in goblet cell density between groups. Quantative RT-PCR of cornea and conjunctiva revealed increased TNF-α expression in IRT5 group (p < 0.001) whereas other markers did not significantly differ from control. IRT5 group had significantly increased species diversity by Shannon index (p = 0.041). Beta diversity of genus by UniFrac principle coordinates analysis showed significant distance between groups (p = 0.001). Compositional differences between groups were observed and some were significantly associated with tear secretion. Multivariate linear regression analysis revealed Christensenellaceae (p = 0.009), Lactobacillus Helveticus group (p = 0.002) and PAC001797_s (p = 0.011) to strongly influence tear secretion.ConclusionIn experimental dry eye model, IRT5 probiotics treatment partially improves experimental dry eye by increasing tear secretion which was associated with and influenced by the change in intestinal microbiome. Also, intestinal microbiome may affect the lacrimal gland through a different mechanism other than regulating inflammation.

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Long Non-coding RNAs Gabarapl2 and Chrnb2 Positively Regulate Inflammatory Signaling in a Mouse Model of Dry Eye.

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