ABSTRACT
Herpes simplex virus-1 (HSV-1) is the leading cause of infectious blindness in the developed world. HSV-1 infection can occur anywhere in the eye, and the most common presentation is epithelial keratitis. In the HSV epithelial keratitis mice model, we detected the expression of TRIM21 and then investigated the clinical relationship between TRIM21 and HSV epithelial keratitis by silencing TRIM21. Through the clinical scores and histopathology examination, we found that TRIM21 can effectively reduce the severity of HSV epithelial keratitis. Furthermore, silencing TRIM21 significantly controlled the virus particle release at 1, 3, and 5 days post-HSV-1 infection. Notably, the production of IFN-ß was enhanced, and the secretion of pro-inflammatory cytokines (IL-6 and TNF-a) was inhibited. Next, human corneal epithelial cells were pretreated with lentivirus or siRNA, respectively, so that TRIM21 expression was overexpressed or silenced. We focused on the regulation of STING-IRF3 and type I interferon signaling after infected with HSV-1. In conclusion, our results have identified that TRIM21 is abnormally high expressed in HSV epithelial keratitis. TRIM21 enhances the replication of HSV-1 in corneal epithelial cells via suppressing the production of type I IFN by inhibiting STING/IRF3 signaling. It also promotes the secretion of IL-6 and TNF-a, thereby aggravating the severity of HSV epithelial keratitis.
ABSTRACT
Purpose: The purpose of this study was to investigate the production of IL-27 p28 and EBI3 in the ocular inflammatory sites, and the role of IL-27 signaling in a model of HSV-1 induced herpetic stromal keratitis (HSK). Methods: The BALB/c mice were injected intraperitoneally (24 h before infection) with anti-IL-27 antibody or IgG antibody as control, infected with HSV-1 via corneal scarification, and then injected intraperitoneally with anti-IL-27 antibody or IgG antibody at 1, 3, and 5 days postinfection. Slit lamp and histopathology were used to assess disease outcome. The levels of IL-27 p28 and EBI3 in corneas were determined by western blotting and immunofluorescence. Furthermore, viral titers were determined, and immune cell infiltrates were collected and analyzed by flow cytometry. Results: We found that the levels of IL-27 p28 and EBI3 in corneas were elevated significantly at the peak of HSK, and both of them were expressed simultaneously in the epithelium, stroma, and endothelium of corneas. In the group of anti-IL-27 treatment, the severity of the corneal lesion and CD4+ T cells infiltration were significantly decreased, and the percentage of CD4+ Foxp3+ Tregs was upregulated markedly in the spleen, DLNs and cornea of HSK mice compared to IgG treatment. Conclusion: These results provided evidence that IL-27 as a pathogenic pro-inflammatory cytokine controlled CD4+ Foxp3+ Tregs production in HSK, which ultimately resulted in promoting the progression of HSK and poor prognosis.