Heme oxygenase 1 attenuates the development of atopic dermatitis–like lesions in mice: Implications for human disease

Background

Oxidative stress has been implicated in the exacerbation of atopic dermatitis (AD).

Objective

We sought to investigate the pathophysiologic roles of inducible antioxidant heme oxygenase (HO) 1 in the development of AD.

Methods

Serum HO-1 levels of patients with AD (n = 100) and age-matched healthy control subjects (n = 72) were determined by means of ELISA. The relationships between serum HO-1 levels and clinical severities, laboratory parameters, and cytokines/chemokines were assessed. Skin lesions of patients with AD and psoriasis were analyzed by means of immunohistochemistry. A murine AD model, DS-Nh, was used to further investigate localization and function of HO-1. Evaluation of symptoms, serum IgE and IL-18 levels, immunoblotting results, and histologic analyses of skin were performed. The effect of intraperitoneally administered hemin, a potent HO-1 inducer, or zinc protoporphyrin IX, an inhibitor of HO, was monitored.

Results

Serum HO-1 levels were significantly increased in patients with AD compared with those seen in healthy control subjects and were associated with AD disease severity. Serum HO-1 levels correlated with serum IgE, lactate dehydrogenase, IL-18, and thymus and activation-regulated chemokine levels. HO-1–expressing cells were accumulated in skin lesions of patients with AD and DS-Nh mice. Immunofluorescence of mouse skin lesions revealed that HO-1–positive cells were macrophages and dendritic cells. Treatment with hemin, but not with zinc protoporphyrin IX, attenuated the development of the skin lesions in DS-Nh mice and reduced serum IL-18 levels.

Conclusion

HO-1 levels were increased in sera and skin lesions of patients with AD. Enhancement of HO-1 attenuated the development of skin lesions in mice, suggesting that HO-1 induction offers a promising therapeutic strategy for AD.

Key words: Atopic dermatitis, heme oxygenase 1, allergy, inflammation

Abbreviations used: AD, Atopic dermatitis, ASD, Adult-onset Still's disease, DC, Dendritic cell, HC, Healthy control subject, HO, Heme oxygenase, HPS, Hemophagocytic syndrome, HRP, Horseradish peroxidase, iNOS, Inducible nitric oxide synthase, LDH, Lactate dehydrogenase, SPF, Specific pathogen-free, TARC, Thymus and activation-regulated chemokine, ZnPP, Zinc protoporphyrin