Heme oxygenase 1 attenuates the development of atopic dermatitis–like lesions in mice: Implications for human disease Mio Kirino, MD, Yohei Kirino, MD,

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Heme oxygenase 1 attenuates the development of atopic dermatitis–like lesions in mice: Implications for human disease Mio Kirino, MD, Yohei Kirino, MD, PhD, Mitsuhiro Takeno, MD, PhD, Yoji Nagashima, MD, PhD, Kazuo Takahashi, MD, PhD, Masayoshi Kobayashi, MD, Shuji Murakami, MD, Tsutomu Hirasawa, DVM, PhD, Atsuhisa Ueda, MD, PhD, Michiko Aihara, MD, PhD, Zenro Ikezawa, MD, PhD, Yoshiaki Ishigatsubo, MD, PhD Journal of Allergy and Clinical Immunology Volume 122, Issue 2, Pages 290-297.e8 (August 2008) DOI: 10.1016/j.jaci.2008.05.031 Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Serum levels of HO-1 in patients with AD (n = 100) and HCs (n = 72; A). Serum levels of HO-1 in patients with AD divided into 4 groups based on their disease severities (B). ∗∗P < .01 and #P < .0001 versus HCs. Horizontal bars indicate mean serum HO-1 values. Relationships between serum HO-1 concentrations and laboratory parameters in patients with AD are shown in the log-log form. Correlations with serum IgE (C), IL-18 (D), LDH (E), and TARC (F) levels were analyzed by means of regression analysis. Journal of Allergy and Clinical Immunology 2008 122, 290-297.e8DOI: (10.1016/j.jaci.2008.05.031) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 HO-1 immunohistochemistry of the skin (×100) from an HC, a patient with AD, and a patient with psoriasis (Pso). Red rectangles indicate enlarged areas (×400), which are shown in the lower part of the figure. HC, 44-year-old man; patient with AD, 68-year-old man, global skin score of 3; patient with psoriasis, 63-year-old man. Journal of Allergy and Clinical Immunology 2008 122, 290-297.e8DOI: (10.1016/j.jaci.2008.05.031) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 HO-1 expression of DS-Nh mice. Photographs of 18-week-old DS-Nh mice maintained under SPF (A), or conventional (conv; B) conditions. Solid squares indicate area with (bottom right) or without (upper left) eruption resected for immunoblottings (see Fig 3, E, conv no. 2). Skin scores (C); serum IgE levels (D). #P < .001 versus the SPF group. Horizontal bars represent mean levels. Immunoblotting of HO-1 and actin from DS-Nh mice skin with or without eruption (E). Densitometric analysis is shown below (means ± SEMs). ∗P < .05 versus the SPF group. Journal of Allergy and Clinical Immunology 2008 122, 290-297.e8DOI: (10.1016/j.jaci.2008.05.031) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Immunofluorescent staining of intact skin from an SPF mouse (A and B) and skin lesion of a conventional DS-Nh mouse (C-H). Fig 4, A, HO-1; Fig 4, B, F4/80; Fig 4, C, HO-1; Fig 4, D, F4/80; Fig 4, E, merged image of HO-1, F4/80, and 4′,6-diamidino-2-phenylindole (×100); Fig 4, F, enlarged view of Fig 4, E, in white square (×200); Fig 4, G, CD11c (×100); Fig 4, H, enlarged view of Fig 4, G, in white square. Merged image of HO-1, CD11c, and 4′,6-diamidino-2-phenylindole (×400). Arrowheads indicate HO-1– and CD11c-positive DCs. Journal of Allergy and Clinical Immunology 2008 122, 290-297.e8DOI: (10.1016/j.jaci.2008.05.031) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Influence of single intraperitoneal administration of PBS, hemin, or ZnPPIX on HO-1 and actin expression in DS-Nh mice. Immunoblotting analysis of skin (A), spleen (B), and lymph nodes (C) of DS-Nh mice (n = 3) treated with PBS, hemin, or ZnPPIX for 24 hours. Immunohistochemistry of HO-1 in DS-Nh mouse skin treated with PBS, hemin, and ZnPPIX (×400; D). Journal of Allergy and Clinical Immunology 2008 122, 290-297.e8DOI: (10.1016/j.jaci.2008.05.031) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Effects of HO-1 inducer or inhibitor on the development of AD-like skin lesions in DS-Nh mice (n = 14). PBS, hemin (4 μmol/L), or ZnPPIX (4 μmol/L) was intraperitoneally injected every week from 6 to 18 weeks of age. A, Skin scores. B, Serum IL-18 levels. C, Serum IgE levels of PBS-, hemin-, and ZnPPIX-treated mice. D, Real-time PCR analysis of iNOS mRNA expressions of spleens. Data are presented as means ± SEMs. RQ, Relative quantity. ∗P < .05 versus the PBS-treated group. Journal of Allergy and Clinical Immunology 2008 122, 290-297.e8DOI: (10.1016/j.jaci.2008.05.031) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Serum levels of HO-1 in patients with AD (n = 100) with or without bronchial asthma, allergic rhinitis, pollinosis, and allergic conjunctivitis. NS, Not significant. Journal of Allergy and Clinical Immunology 2008 122, 290-297.e8DOI: (10.1016/j.jaci.2008.05.031) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Comparison between serum HO-1 concentrations and laboratory parameters in patients with AD (n = 100) are shown in log-log form. Correlations with serum WBC (A), monocyte count (B), neutrophil count (C), and eosinophil count (D) were analyzed by means of regression analysis. Journal of Allergy and Clinical Immunology 2008 122, 290-297.e8DOI: (10.1016/j.jaci.2008.05.031) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Comparison between serum HO-1 concentrations and cytokine levels in patients with AD are shown in log-log form. Correlations with serum IFN-γ (A), IL-4 (B), and IL-10 (C) were analyzed by means of regression analysis. Journal of Allergy and Clinical Immunology 2008 122, 290-297.e8DOI: (10.1016/j.jaci.2008.05.031) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Comparison between serum levels of IL-18 and global skin scores in patients with AD divided into 4 groups based on their disease severities. Journal of Allergy and Clinical Immunology 2008 122, 290-297.e8DOI: (10.1016/j.jaci.2008.05.031) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Immunofluorescent staining of intact skin from 6-week-old SPF DS-Nh mice. A, HO-1. B, Normal rabbit serum. C, F4/80. D, Normal rat serum (×200). DAPI, 4′,6-Diamidino-2-phenylindole. Journal of Allergy and Clinical Immunology 2008 122, 290-297.e8DOI: (10.1016/j.jaci.2008.05.031) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Immunofluorescent staining of skin from 7-week-old SPF DS-Nh mice treated with PBS (A and B) or hemin (C-F) for 24 hours. Fig E6, A, HO-1; Fig E6, B, F4/80; Fig E6, C, 4′,6-diamidino-2-phenylindole; Fig E6, D, F4/80; Fig E6, E, HO-1; and Fig E6, F, merged image of HO-1, F4/80, and 4′,6-diamidino-2-phenylindole (×200). Arrowheads indicate HO-1– and F4/80-positive macrophages. Journal of Allergy and Clinical Immunology 2008 122, 290-297.e8DOI: (10.1016/j.jaci.2008.05.031) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Comparison between serum IL-18 levels and skin scores in DS-Nh mice treated with PBS, hemin, or ZnPPIX (n = 14 for each group). Journal of Allergy and Clinical Immunology 2008 122, 290-297.e8DOI: (10.1016/j.jaci.2008.05.031) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions