Abstract
To investigate the role of miRNA in the pathogenesis underlying ocular surface complications in patients with Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) in the chronic stage. Using oligonucleotide microarrays, we performed comprehensive miRNA analysis of the conjunctival epithelium of SJS/TEN patients with severe ocular complications (SOC) in the chronic stage (n = 3). Conjunctival epithelium of patients with conjunctival chalasis (n = 3) served as the control. We confirmed the down- and up-regulation of miRNA of interest by quantitative real-time polymerase chain reaction (RT-PCR) assays using the conjunctival epithelium from 6 SJS/TEN with SOC patients and 7 controls. We focused on miRNA-455-3p, which is significantly upregulated in the conjunctival epithelium of the SJS/TEN patients, and investigated its function by inhibiting miR-455-3p in primary human conjunctival epithelial cells (PHCjEs). Comprehensive miRNA expression analysis showed that the expression of 5 kinds of miRNA was up-regulated more than fivefold, and that the expression of another 5 kinds of miRNA was down-regulated by less than one-fifth. There was a significant difference between the SJS/TEN patients and the controls [analysis of variance (ANOVA) p < 0.05]. Quantitative miRNA PCR assay showed that hsa-miR-31* and hsa-miR-455-3p were significantly up-regulated in the conjunctival epithelium of the SJS/TEN patients. Comprehensive gene expression analysis of PHCjEs transfected with the hsa-miR-455-3p inhibitor and quantitative RT PCR assay showed that ANKRD1, CXCL8, CXCL2, GEM, PTGS2, RNASE8, IL6, and CXCL1 were down-regulated by the hsa-miR-455-3p inhibitor. Quantitative RT-PCR, focused on the genes that tended to be up-regulated in SJS/TEN with SOC, revealed that the expression of IL1A, KPRP, IL36G, PPP1R3C, and ADM was significantly down-regulated in PHCjEs transfected with the hsa-miR-455-3p inhibitor. Our results suggest that miRNA-455-3p could regulate many genes including innate immune related genes in human conjunctival epithelium, and that its up-regulation contributes to the pathogenesis on the ocular surface in SJS/TEN patients with the SOC in the chronic stage. Our findings may lead to the development of new treatments using the miRNA-455-3p inhibitor.
Highlights
To investigate the role of miRNA in the pathogenesis underlying ocular surface complications in patients with Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) in the chronic stage
We found that 52 miRNAs were up-regulated more than fivefold; there was a significant difference between the SJS/TEN patients and the controls [p < 0.05 by analysis of variance (ANOVA)]
We found that 13 miRNAs were down-regulated by less than one-fifth and that there was a significant difference between the SJS/ TEN patients and the controls (p < 0.05, ANOVA) (Supplemental Table 1b)
Summary
To investigate the role of miRNA in the pathogenesis underlying ocular surface complications in patients with Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) in the chronic stage. We performed comprehensive miRNA analysis of the conjunctival epithelium of SJS/TEN patients with severe ocular complications (SOC) in the chronic stage (n = 3). Quantitative miRNA PCR assay showed that hsa-miR-31* and hsa-miR-455-3p were significantly up-regulated in the conjunctival epithelium of the SJS/TEN patients. Our results suggest that miRNA-455-3p could regulate many genes including innate immune related genes in human conjunctival epithelium, and that its up-regulation contributes to the pathogenesis on the ocular surface in SJS/TEN patients with the SOC in the chronic stage. The diagnosis of SJS/TEN by ophthalmologists has been based on a confirmed history of acute-onset high fever, serious mucocutaneous illness with skin eruptions, and involvement of at least 2 mucosal sites including the ocular surface[2,4,5,10,11,12] They tend to describe both SJS and TEN with SOC broadly as “SJS”9
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