2. Academic Validation
  3. Targeting Type I IFN/STAT1 signaling inhibited and reversed corneal squamous metaplasia in Aire-deficient mouse

Targeting Type I IFN/STAT1 signaling inhibited and reversed corneal squamous metaplasia in Aire-deficient mouse

  • Pharmacol Res. 2022 Dec 16;187:106615. doi: 10.1016/j.phrs.2022.106615.
Yaoyao Yu 1,  Shengqian Dou 2,  Peng Peng 3,  Li Ma 2,  Xia Qi 2,  Ting Liu 2,  Yang Yu 2,  Chao Wei 4,  Weiyun Shi 5
Affiliations

Affiliations

  • 1 Medical College of Qingdao University, Qingdao, China; State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China.
  • 2 State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China.
  • 3 State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China; School of Ophthalmology, Shandong First Medical University, Jinan, China.
  • 4 State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China. Electronic address: chaowei_82@163.com.
  • 5 State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China; Eye Hospital of Shandong First Medical University (Shandong Eye Hospital), Jinan, China; School of Ophthalmology, Shandong First Medical University, Jinan, China. Electronic address: weiyunshi@163.com.
PMID: 36535573 DOI: 10.1016/j.phrs.2022.106615
Abstract

Corneal transparency and integrity are essential for obtaining good vision; nevertheless, squamous metaplasia (SQM) of ocular epithelium is a kind of serious blinding corneal diseases, without therapeutic medication in clinic. Here, we found that deficiency of the autoimmune regulator (AIRE) in corneas spontaneously developed corneal plaques. Using corneal abrasion model, we revealed that deletion of Aire not only resulted in delayed corneal re-epithelialization, but also promoted a cell-fate transition from transparent corneal epithelium to keratinized epithelium, histopathologically characterized with SQM based on the transcriptomic analysis. Mechanistically, Aire-deficient corneas led to the heightened Type I interferon (IFN-I)/STAT1 signaling after abrasion. Pharmacological blockade of IFN-I/JAK/STAT1 signaling in Aire-knockout (KO) corneas not only accelerated epithelial wound healing, but also alleviated corneal plaques and SQM. Collectively, our findings revealed critical roles of AIRE in governing corneal epithelial homeostasis and pathologic keratinization, and further identified IFN-I/STAT1 signaling as a potential target for treating ocular surface diseases with SQM, and even for treating pathological scenarios related to SQM in other tissues.

Keywords

Aire-knockout mice; Corneal homeostasis; Fludarabine (PubChem CID: 657237); IFN alpha-IFNAR-IN-1 (hydrochloride) (PubChem CID: 72193873); IFN-I signaling; JAK/STAT1 signaling; Squamous metaplasia (SQM).

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