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Topical hypochlorite ameliorates NF-κB–mediated skin diseases in mice
Thomas H. Leung, … , Susan J. Knox, Seung K. Kim
Thomas H. Leung, … , Susan J. Knox, Seung K. Kim
Published November 15, 2013
Citation Information: J Clin Invest. 2013;123(12):5361-5370. https://doi.org/10.1172/JCI70895.
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Research Article Genetics

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.

Authors

Thomas H. Leung, Lillian F. Zhang, Jing Wang, Shoucheng Ning, Susan J. Knox, Seung K. Kim

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Hypochlorite induces Systemic Sclerosis in the mouse

Submitter: Niloufar Kavian | niloufar.kavian@cch.aphp.fr

Authors: Amélie Servettaz, Philippe Guilpain, Frédéric Batteux

Hôpital Cochin, GH Paris-Centre

Published December 11, 2013

Hypochlorous acid (HOCl) is an oxidizer widely used as bleach. HOCl, produced in neutrophils through the myeloperoxydase-catalysed oxidation of chloride by hydrogen peroxide, is pivotal in the defence against bacteria (1). HOCl is rapidly transformed into hydroxyl radical (OH°), that can react with a large variety of proteins and nucleic acids. Hydroxyl radical is the most reactive and the strongest oxidant molecule of all reactive oxygen species (ROS).

Leung et al. have recently reported that HOCl inhibits the activation of NF-kB through the oxidation of IKK in cultured keratinocytes, and attenuates skin lesions in two mouse models of NF-kB-driven epidermal diseases (2). Furthermore, HOCl induces epidermal hyperplasia and keratinocyte proliferation in the skin of aged mice, thus suggesting that HOCl could be a therapeutic tool in such skin diseases.

Since HOCl is presented here as a potential therapeutic agent in skin diseases, it must be stressed that exposure of skin to HOCl can also be terribly hazardous. Indeed, we have shown in 2009 that daily injections of HOCl into the skin of mice can induce in six weeks almost all the clinical and biological features of systemic sclerosis (SSc) (3). Those mice develop an extensive skin and lung fibrosis with differentiation of fibroblasts into myofibroblasts that produce high amounts of collagen, express α-Smooth Muscle Actin and overproliferate exactly as  observed in the skin and lungs of SSc patients (4-6) (See also, Figure 1). Mice also develop the vasculopathy observed in SSc, with increased levels of serum sVCAM and sE-selectin (6-8). The inflammatory and autoimmune process that develops in those mice leads to increased levels of splenic B cells, production of the SSc-specific anti-topoisomerase-1 antibodies, skin and lung infiltration by T cells, and increased exhaled NO as in patients with SSc (3, 8-10).

If the paper by Leung et al. reports the hyperproliferative effects of HOCl on keratinocytes and an increased epidermal thickness, it presents no data on fibroblasts or dermis. Although the two protocols differ by the route of administration (intradermal injection versus skin exposure), the duration and the concentration of HOCl, the dramatic effects on keratinocytes after only two weeks in the paper by Leung et al., along with the lack of data on dermal impact must prompt clinical investigators to be very cautious if they decide to try such protocol in humans as suggested by the authors.

 

Footnotes

The authors declare no conflicts of interest.

 

 

1.         Winterbourn, C.C. 2002. Biological reactivity and biomarkers of the neutrophil oxidant, hypochlorous acid. Toxicology 181-182:223-227.

2.         Leung, T.H., Zhang, L.F., Wang, J., Ning, S., Knox, S.J., and Kim, S.K. 2013 Topical hypochlorite ameliorates NF-kappaB-mediated skin diseases in mice. J Clin Invest 123:5361-5370.

3.         Servettaz, A., Goulvestre, C., Kavian, N., Nicco, C., Guilpain, P., Chéreau, C., Vuiblet, V., Guillevin, L., Mouthon, L., Weill, B., et al. 2009. Selective oxidation of DNA topoisomerase 1 induced systemic sclerosis in the mouse. J Immunol 182:5855-5864.

4.         Simonini, G., Matucci Cerinic, M., Generini, S., Zoppi, M., Anichini, M., Cesaretti, C., Pignone, A., Falcini, F., Lotti, T., and Cagnoni, M. 1999. Oxidative stress in Systemic Sclerosis. Mol Cell Biochem 196:85-91.

5.         Kavian, N., Servettaz, A., Mongaret, C., Wang, A., Nicco, C., Chéreau, C., Grange, P., Vuiblet, V., Birembaut, P., Diebold, M.D., et al. 2010. Targeting ADAM-17/notch signaling abrogates the development of systemic sclerosis in a murine model. Arthritis Rheum 62:3477-3487.

6.         Kavian, N., Marut, W., Servettaz, A., Nicco, C., Chereau, C., Lemarechal, H., Borderie, D., Dupin, N., Weill, B., and Batteux, F. 2012. Reactive oxygen species-mediated killing of activated fibroblasts by arsenic trioxide ameliorates fibrosis in a murine model of systemic sclerosis. Arthritis Rheum 64:3430-3440.

7.         Kavian, N., Servettaz, A., Marut, W., Nicco, C., Chereau, C., Weill, B., and Batteux, F. 2011. Sunitinib inhibits the phosphorylation of PDGF-receptor beta in the skin of mice with scleroderma-like features and prevents the development of the disease. Arthritis Rheum.

8.         Marut, W.K., Kavian, N., Servettaz, A., Nicco, C., Ba, L.A., Doering, M., Chereau, C., Jacob, C., Weill, B., and Batteux, F. 2012. The organotelluride catalyst (PHTE)(2)NQ prevents HOCl-induced systemic sclerosis in mouse. J Invest Dermatol 132:1125-1132.

9.         Servettaz, A., Kavian, N., Nicco, C., Deveaux, V., Chéreau, C., Wang, A., Zimmer, A., Lotersztajn, S., Weill, B., Batteux, F., et al. 2010. Targeting the cannabinoid pathway limits the development of fibrosis and autoimmunity in a mouse model of systemic sclerosis. Am J Pathol. 177:187-196.

10.       Marut, W., Kavian, N., Servettaz, A., Hua-Huy, T., Nicco, C., Chereau, C., Weill, B., Dinh-Xuan, A.T., and Batteux, F. 2013. Amelioration of systemic fibrosis in mice by angiotensin II receptor blockade. Arthritis Rheum 65:1367-1377.

 

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