Overexpression of HE4/WFDC2 gene in mice leads to keratitis and corneal opacity.

HE4 is overexpressed in malignant lesions, and elevated serum HE4 levels have been applied as a biomarker for gynecologic cancers. While previous studies have demonstrated the HE4 activities in cancer biology, its role(s) in benign disease is unclear. In current study, we characterize the keratopathy phenotype of transgenic mice with HE4 overexpression (HE4-OE). HE4-OE mice started to display signs of keratitis such as eye-scratching, conjunctiva inflammation, red eyes, periocular secretions, and rough skin/hair loss around the eyes at 3 months after birth. All the mice suffered keratitis, severe corneal opacity and ELISA results indicated HE4 overexpression, and significantly increased IL-6 and TNF-α levels in the cornea. Immunostaining demonstrated the accumulation of disorganized collagen fibers, fibroblast activation, and the presence of vessel-like structures, indicating the progression of corneal opacification. The cornea alkali burn model showed increased HE4 expression, which was accompanied by the elevation of IL-6 and TNF-α in the cornea. Thus, both the HE4-OE and alkali burn models have correlated increased HE4 expression to inflammatory responses. These studies indicate that HE4 may play a significant role(s) in keratopathy and other physiopathological conditions of the eye.