Investigative Ophthalmology & Visual Science · 7 authors, 1 centre
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In a mouse dry eye model and in human corneal epithelial cells, IFN-γ activated the JAK2/STAT1 signaling pathway to promote pyroptosis, while genetic deletion of Ifng or pharmacological STAT1 inhibition reduced pyroptosis markers and alleviated dry eye symptoms.
This preclinical study investigated the role of IFN-γ in corneal epithelial pyroptosis using a desiccating stress-induced dry eye mouse model in wild-type and Ifng-knockout C57BL/6 mice, as well as an immortalized human corneal epithelial cell line (HCE-T) under hyperosmolar stress. RNA-seq and qRT-PCR demonstrated upregulation of IFNG and IFN-γ-responsive genes in corneas of dry eye mice. Genetic deletion of Ifng reduced corneal defects, enhanced tear secretion, and reduced goblet cell loss. Topical STAT1 inhibition in vivo and STAT1 siRNA in vitro suppressed pyroptosis markers. ROS levels were elevated in dry eye, and scavenging ROS with NAC reduced pyroptosis, with evidence positioning oxidative stress downstream of JAK2/STAT1. Limitations include the use of an immortalized cell line, the inability to fully distinguish direct epithelial effects from immune cell-mediated effects in vivo, and the preclinical nature of the findings.
