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Topical hypochlorite ameliorates NF-κB-mediated skin diseases in mice
Abstract:
Nuclear factor-κB (NF-κB) regulates cellular responses to inflammation and aging, and alterations in NF-κB signaling underlie the pathogenesis of multiple human diseases. Effective clinical therapeutics targeting this pathway remain unavailable. In primary human keratinocytes, we found that hypochlorite (HOCl) reversibly inhibited the expression of CCL2 and SOD2, two NF-κB-dependent genes. In cultured cells, HOCl inhibited the activity of inhibitor of NF-κB kinase (IKK), a key regulator of NF-κB activation, by oxidizing cysteine residues Cys114 and Cys115. In NF-κB reporter mice, topical HOCl reduced LPS-induced NF-κB signaling in skin. We further evaluated topical HOCl use in two mouse models of NF-κB-driven epidermal disease. For mice with acute radiation dermatitis, topical HOCl inhibited the expression of NF-κB-dependent genes, decreased disease severity, and prevented skin ulceration. In aged mice, topical HOCl attenuated age-dependent production of p16INK4a and expression of the DNA repair gene Rad50. Additionally, skin of aged HOCl-treated mice acquired enhanced epidermal thickness and proliferation, comparable to skin in juvenile animals. These data suggest that topical HOCl reduces NF-κB-mediated epidermal pathology in radiation dermatitis and skin aging through IKK modulation and motivate the exploration of HOCl use for clinical aims.
Insights
Hypochlorite (HOCl) applied topically inhibits nuclear factor-kappa B (NF-κB) signaling. This treatment reduces inflammation and improves skin aging, suggesting potential clinical applications for NF-κB-driven diseases.
Area of Science:
- Immunology
- Dermatology
- Molecular Biology
Background:
- Nuclear factor-kappa B (NF-κB) signaling is crucial for cellular responses to inflammation and aging.
- Dysregulation of NF-κB contributes to numerous human diseases, yet effective targeted therapies are lacking.
- NF-κB controls the expression of key genes involved in inflammation and cellular processes.
Purpose of the Study:
- To investigate the therapeutic potential of hypochlorite (HOCl) in modulating NF-κB signaling in skin.
- To evaluate the efficacy of topical HOCl in preclinical models of NF-κB-driven skin conditions.
Main Methods:
- Primary human keratinocytes and NF-κB reporter mice were used to study HOCl effects.
- HOCl's impact on inhibitor of NF-κB kinase (IKK) activity and NF-κB-dependent gene expression was assessed.
- Topical HOCl was applied to mouse models of radiation dermatitis and skin aging.
Main Results:
- HOCl reversibly inhibited NF-κB-dependent genes (CCL2, SOD2) and IKK activity in cultured cells.
- Topical HOCl reduced NF-κB signaling in mouse skin and ameliorated radiation dermatitis, preventing ulceration.
- In aged mice, HOCl attenuated age-related molecular changes and promoted skin rejuvenation.
Conclusions:
- Topical HOCl effectively modulates NF-κB signaling via IKK inhibition.
- HOCl demonstrates therapeutic potential for NF-κB-mediated skin pathologies, including radiation dermatitis and aging.
- These findings support further investigation of HOCl for clinical applications in dermatology.
