Potential Roles of Extracellular Granzyme B in Corneal and Conjunctival Diseases: A Narrative Review

The cornea and conjunctiva are critical structures of the ocular surface that are prone to a range of inflammatory diseases impacting the vision of millions globally. Moreover, due to their complex etiology and pathophysiology, these conditions remain a significant clinical challenge. Granzyme B (GrB), a serine protease traditionally recognized for its intracellular role in targeting tumor or pathogen-infected cells, has been implicated in numerous pathogenic mechanisms observed in inflammatory corneal and conjunctival diseases, such as dysregulated inflammation and tissue remodeling, barrier dysfunction, epithelial-to-mesenchymal transition (EMT), fibrosis, neovascularization, and cell death, through its extracellular activity by cleaving various substrates upon being released into the extracellular space. On the ocular surface, GrB has been found to be upregulated in several inflammatory conditions, including keratolysis, herpes simplex keratitis (HSK), corneal graft rejection, pterygium, Stevens-Johnson syndrome (SJS), and even keratoconus, where it may contribute to chronic inflammation, epithelial barrier dysfunction, dysregulated tissue remodeling, and fibrosis. Although recent research has explored both classic immune-mediated intracellular roles and emerging extracellular roles of GrB across different tissues, organs, and diseases, its role in ocular diseases, particularly in the cornea and conjunctiva, remains understudied. This review aims to consolidate current knowledge on GrB's role in ocular surface diseases and explore its potential contributions to corneal and conjunctival pathologies by integrating findings from both ocular and systemic diseases to explore its molecular mechanisms, cellular sources, and extracellular substrates.