Senescence-Driven IL-17A Inflammatory Circuit Promotes Epithelial-Mesenchymal Transition (EMT) and Progression in Age-Related Posterior Subcapsular Cataracts.

Abstract

Cataract is a leading cause of visual impairment worldwide, and its prevalence is increasing with population aging. The majority are age-related cataracts (ARC), clinically classified into nuclear, cortical, and posterior subcapsular cataracts (PSC) by opacity location. Mechanisms of cataractogenesis remain incompletely understood. While cortical and nuclear cataracts are largely attributed to crystallin aggregation, such protein-centric mechanisms fail to explain the early onset and axial location of PSC. Morphologically, PSC resembles posterior capsule opacification (PCO), a secondary cataract driven by epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs), suggesting LEC-EMT may also contribute to PSC. Using clinically stratified human lens samples, we confirmed EMT marker expression across PSC subtypes. Transcriptomic profiling revealed that LECs, the lens's sole metabolically active cells, in age-related PSC (ARC-PSC), compared with age-related nuclear cataract (ANC) and clear lenses, exhibit elevated EMT signatures tightly linked to senescence-associated inflammatory signaling. Aqueous humor (AqH) profiling demonstrated a pro-inflammatory milieu across PSC subtypes, with IL-17A uniquely elevated in ARC-PSC, consistent with transcriptomic findings. Integrated analyses support a model in which senescence functions as an upstream driver, whereby senescent LECs release SASP factors, including IL-17A, that activate NF-κB signaling to amplify inflammation, reinforce senescence, and drive EMT. In vitro, senolysis and IL-17A blockade disrupted this loop, attenuating senescence- and EMT-associated phenotypes. Collectively, our study demonstrates that senescent LECs sustain an IL-17A-NF-κB circuit that drives EMT and accelerates ARC-PSC progression, positioning ARC-PSC as a unique human context to study senescence-induced epithelial remodeling in aging tissues.