Canonical NF-κB signaling maintains corneal epithelial integrity and prevents corneal aging via retinoic acid

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Abstract

Disorders of the transparent cornea affect millions of people worldwide. However, how to maintain and/or regenerate this organ remains unclear. Here, we show that Rela (encoding a canonical NF-kB subunit) ablation in K14⁺ corneal epithelial stem cells not only disrupts corneal regeneration but also results in age-dependent epithelial deterioration, which triggers aberrant wound healing processes including stromal remodeling, neovascularization, epithelial metaplasia, and plaque formation at the central cornea. These anomalies are largely recapitulated in normal mice that age naturally. Mechanistically, Rela deletion suppresses expression of Aldh1a1, an enzyme required for retinoic acid synthesis from vitamin A. Retinoic acid administration blocks development of ocular anomalies in Krt14-Cre; Rela^f/f mice and naturally aged mice. Moreover, epithelial metaplasia and plaque formation are preventable by inhibition of angiogenesis. This study thus uncovers major mechanisms governing corneal maintenance, regeneration and aging and identifies the NF-kB-retinoic acid pathway as a therapeutic target for corneal disorders.

Data availability

Sequencing data have been deposited in GEO database (NCBI) under the accession Series GSE161433

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Qian Yu

Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Soma Biswas

Department of Ophthalmology, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1427-2678
Gang Ma

Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Peiquan Zhao

Department of Ophthalmology, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Baojie Li

Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China

For correspondence
libj@sjtu.edu.cn

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3913-1062
Jing Li

Department of Ophthalmology, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

For correspondence
lijing@xinhuamed.com.cn

Competing interests
The authors declare that no competing interests exist.

Funding

National Key Research and Development Program of China (2018YFA0800801)

Baojie Li

National Key Research and Development Program of China (2018YFA0800803)

Baojie Li

National Natural Science Foundation of China (81520108012)

Baojie Li

National Natural Science Foundation of China (91749201)

Baojie Li

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All the mouse work was carried out following the recommendations by the National Research Council Guide for the Care and Use of Laboratory Animals, with the protocols approved by the Institutional Animal Care and Use Committee of Shanghai, China [SYXK(SH)2011-0112].

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.