Abstract
Purpose :
Pterygium is known to cause significant ocular discomfort and vision decline. Currently, surgical excision, with its associated risks such as infection, corneoscleral thinning and recurrence, remains the only treatment option. While ultraviolet (UV) exposure is a known risk factor, its mechanistic role in pterygium pathogenesis remains unclear. We propose that chronic UV exposure triggers the de-repression of retroelements, including human endogenous retroviruses (HERVs) and long interspersed nuclear elements (LINEs). Once de-repressed, these retroelements can promote cellular inflammation through double-stranded RNA (dsRNA) and DNA (dsDNA). This results in the activation of dsRNA and dsDNA sensors, notably RIG-I/MDA5/MAVS and the cGAS-STING pathways. Aberrant activation of these innate immune pathways can induce cell migration and proliferation.
Methods :
We analyzed bulk RNA-sequencing data from 16 pterygium and healthy conjunctiva samples, focusing on differential expression and pathway analysis. Utilizing Telescope for retroelement identification and DESeq2 for differential expression analysis, we investigated HERVs and LINE-1 elements. Human conjunctival fibroblast cells were exposed to varying intensities of UV-B radiation (0, 100, 200, 500 J/m2) for five days. At day 6, RNA was extracted for sequencing and analysis. Wound-scratch assays were also conducted to assess UV-induced migration alterations.
Results :
Differential expression of HERVs and LINE-1 elements was observed in pterygium. Hierarchical clustering based on these elements differentiated pterygium from normal conjunctiva. Transcriptomic analysis via Ingenuity Pathway Analysis (IPA) indicated activation of RIG-I/MDA5/MAVS and cGAS-STING pathways in pterygium. However, UV exposure in cultured fibroblasts resulted in only modest changes in retroelement expression. Scratch assays showed no significant migration differences between UV-exposed and non-exposed fibroblasts.
Conclusions :
Differential expression of retroelements in human pterygium correlates with activation of innate immune pathways. Our data indicates the insufficiency of UV alone in activating the dsRNA and dsDNA sensors. These findings provide mechanistic insights into the pathogenesis of pterygium, potentially identifying novel therapeutic targets.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.