Interferon-γ elicits the ocular surface pathology mimicking dry eye through direct modulation of resident corneal cells

Abstract

Despite accumulating evidence indicating a key role of interferon-γ (IFN-γ)-producing immune cells in ocular infection and immunity, little is known about the direct effects of IFN-γ on resident corneal cells or on the ocular surface. Here, we report that IFN-γ impacts corneal stromal fibroblasts and epithelial cells to promote inflammation, opacification, and barrier disruption on the ocular surface, leading to dry eye. Our results demonstrated that IFN-γ dose-dependently induced cytotoxicity, pro-inflammatory cytokine/chemokine production, and expression of major histocompatibility complex class II and CD40 in cultures of corneal stromal fibroblasts and epithelial cells while increasing myofibroblast differentiation of corneal stromal fibroblasts. In mice, subconjunctival IFN-γ administration caused corneal epithelial defects and stromal opacity in dose- and time-dependent manners while promoting neutrophil infiltration and inflammatory cytokine expression in the cornea. Moreover, IFN-γ reduced aqueous tear secretion and the number of conjunctival goblet cells responsible for mucinous tear production. Together, our findings suggest that IFN-γ induces the ocular surface changes characteristic of dry eye disease at least in part through its direct effects on resident corneal cells.

CD4+T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model

“…IFN-γ and IL-17 are pathogenic to the corneal epithelium (19,27,29), and conjunctival NK cells and other innate immune cells represent a significant source of these cytokines in the ocular surface (30,(34)(35)(36)(37). Using a non-surgical DED model, Coursey et al (35) showed that conjunctival IFN-γ and Th1-associated chemokines in Rag1KO mice increase after 5 days of desiccating stress but return to baseline levels by day 10.…”

“…Effector CD4 + T cells in DED are mostly Th1 and Th17 (14,15), which promote type 1 and type 3 immunity, respectively (23), by releasing proinflammatory cytokines and recruiting other immune cells (23,24). IFN-γ, a hallmark type 1 cytokine, exerts a deleterious effect on the ocular surface by promoting both the apoptosis of conjunctival goblet cells and corneal epithelial cells and the squamous metaplasia of corneal epithelial cells (12,(25)(26)(27)(28)(29). IL-17, a hallmark type 3 cytokine, induces corneal epithelial cells to secrete matrix metalloproteinases, which degrade intercellular junctions and lead to corneal barrier disruption (19,30).…”

“…IL-17 also favors corneal lymphangiogenesis, which facilitates the migration of corneal antigen-presenting cells and, thus, pathogenic immune responses (31). IFN-γ and IL-17 have additional effects on corneal and conjunctival epithelial, stromal, and immune cells that amplify ocular surface inflammation and tissue damage (29). However, it should be noted that CD4 + T cells are not the only source of the pathogenic IFN-γ and IL-17 in the ocular surface because CD8 + T cells, γδ T cells, NK cells, and other innate lymphoid cells also secrete these cytokines (32,33).…”

Podcast on Cross-speciality Perspectives on Practical Management of Atopic Dermatitis-Associated Ocular Surface Diseases

“…The other thought is that the blocking of IL-4 pathways may be driving more of a type 1 response on the eye [ 21 ]. That type 1 response is driven by cytokines, such as interferon-gamma, and those are definitely known to drive ocular surface scarring, [activation] of cytotoxic T cells, and accumulation of cytotoxic T cells on the ocular surface [ 22 , 23 ], which can [cause] the signs of inflammation and drive advanced ocular surface changes, such as scarring and neovascularization of the cornea [ 24 ].…”