Canonical NF-κB signaling maintains corneal epithelial integrity and prevents corneal aging via retinoic acid.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34085926.
- Also identified by DOI 10.7554/eLife.67315 and PMC identifier 8192125.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 <i>Rela</i> (encoding a canonical NF-κB subunit) ablation in K14<sup>+</sup> 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, <i>Rela</i> deletion suppresses expression of Aldh1a1, an enzyme required for retinoic acid synthesis from vitamin A. Retinoic acid administration blocks development of ocular anomalies in <i>Krt14-Cre; Rela<sup>f/f</sup></i> mice and naturally aged mice. Moreover, epithelial metaplasia and plaque formation are preventable by inhibition of angiogenesis. This study thus uncovers the major mechanisms governing corneal maintenance, regeneration, and aging and identifies the NF-κB-retinoic acid pathway as a therapeutic target for corneal disorders.
Medical subject headings
- Age Factors
- Aldehyde Dehydrogenase 1 Family
- Aldehyde Dehydrogenase 1 Family/genetics
- Aldehyde Dehydrogenase 1 Family/metabolism
- Animals
- Burns, Chemical
- Burns, Chemical/drug therapy
- Burns, Chemical/etiology
- Burns, Chemical/metabolism
- Burns, Chemical/pathology
- Cell Differentiation
- Cell Differentiation/drug effects
- Cell Proliferation
- Cell Proliferation/drug effects
- Cells, Cultured
- Cellular Senescence
- Cellular Senescence/drug effects
- Corneal Neovascularization
- Corneal Neovascularization/metabolism
- Corneal Neovascularization/pathology
- Corneal Neovascularization/prevention & control
- Corneal Stroma
- Corneal Stroma/drug effects
- Corneal Stroma/metabolism
- Corneal Stroma/pathology
- Disease Models, Animal
- Epithelium, Corneal
- Epithelium, Corneal/drug effects
- Epithelium, Corneal/metabolism
- Epithelium, Corneal/pathology
- Eye Burns
- Eye Burns/chemically induced
- Eye Burns/drug therapy
- Eye Burns/metabolism
- Eye Burns/pathology
- Mice, Knockout
- Regeneration
- Regeneration/drug effects
- Retinal Dehydrogenase
- Retinal Dehydrogenase/genetics
- Retinal Dehydrogenase/metabolism
- Signal Transduction
- Stem Cells
- Stem Cells/drug effects
- Stem Cells/metabolism
- Stem Cells/pathology
- Transcription Factor RelA
- Transcription Factor RelA/genetics
- Transcription Factor RelA/metabolism
- Tretinoin
- Tretinoin/pharmacology
- Mice