Human β-defensin-3 attenuates atopic dermatitis–like inflammation through autophagy activation and the aryl hydrocarbon receptor signaling pathway
Ge Peng, Saya Tsukamoto, Risa Ikutama, Hai Le Thanh Nguyen, Yoshie Umehara, Juan V. Trujillo-Paez, Hainan Yue, Miho Takahashi, Takasuke Ogawa, Ryoma Kishi, Mitsutoshi Tominaga, Kenji Takamori, Jiro Kitaura, Shun Kageyama, Masaaki Komatsu, Ko Okumura, Hideoki Ogawa, Shigaku Ikeda, François Niyonsaba
Ge Peng, Saya Tsukamoto, Risa Ikutama, Hai Le Thanh Nguyen, Yoshie Umehara, Juan V. Trujillo-Paez, Hainan Yue, Miho Takahashi, Takasuke Ogawa, Ryoma Kishi, Mitsutoshi Tominaga, Kenji Takamori, Jiro Kitaura, Shun Kageyama, Masaaki Komatsu, Ko Okumura, Hideoki Ogawa, Shigaku Ikeda, François Niyonsaba
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Research Article Dermatology Inflammation

Human β-defensin-3 attenuates atopic dermatitis–like inflammation through autophagy activation and the aryl hydrocarbon receptor signaling pathway

Abstract

Human β-defensin-3 (hBD-3) exhibits antimicrobial and immunomodulatory activities; however, its contribution to autophagy regulation remains unclear, and the role of autophagy in the regulation of the epidermal barrier in atopic dermatitis (AD) is poorly understood. Here, keratinocyte autophagy was restrained in the skin lesions of patients with AD and murine models of AD. Interestingly, hBD-3 alleviated the IL-4– and IL-13–mediated impairment of the tight junction (TJ) barrier through keratinocyte autophagy activation, which involved aryl hydrocarbon receptor (AhR) signaling. While autophagy deficiency impaired the epidermal barrier and exacerbated inflammation, hBD-3 attenuated skin inflammation and enhanced the TJ barrier in AD. Importantly, hBD-3–mediated improvement of the TJ barrier was abolished in autophagy-deficient AD mice and in AhR-suppressed AD mice, suggesting a role for hBD-3–mediated autophagy in the regulation of the epidermal barrier and inflammation in AD. Thus, autophagy contributes to the pathogenesis of AD, and hBD-3 could be used for therapeutic purposes.

Authors

Ge Peng, Saya Tsukamoto, Risa Ikutama, Hai Le Thanh Nguyen, Yoshie Umehara, Juan V. Trujillo-Paez, Hainan Yue, Miho Takahashi, Takasuke Ogawa, Ryoma Kishi, Mitsutoshi Tominaga, Kenji Takamori, Jiro Kitaura, Shun Kageyama, Masaaki Komatsu, Ko Okumura, Hideoki Ogawa, Shigaku Ikeda, François Niyonsaba

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Figure 1

Autophagy-related proteins are dysregulated in AD skin lesions.

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Autophagy-related proteins are dysregulated in AD skin lesions. (A) Immu...
(A) Immunofluorescence staining of LC3 and p62 in the epidermis of patients with AD and normal participants. Representative immunofluorescence images of skin (left) and quantification of the staining intensity in the epidermis (right). The white dashed line indicates the basement membrane between the epidermis and dermis. Scale bars: 50 or 100 μm; n = 5 per group. (B) Immunofluorescence staining of LC3 and p62 in the epidermis of DNCB-treated AD mice and normal mice. Representative immunofluorescence images of skin (left) and quantification of the staining intensity in the epidermis (right). The white dashed line indicates the basement membrane between the epidermis and dermis. Scale bars: 20 μm; n = 3–6 per group. (C) Expression of p62 and LC3 in the back skins of DNCB-induced AD mice and normal mice; n = 6 per group. Representative immunoblots of the indicated proteins from mouse skin lysates (left) and quantification of the band intensities of LC3 and p62 (right). GAPDH was used as a loading control. (D) Representative electron microscopic images of keratinocytes in lesional skin from DNCB-induced AD mice and keratinocytes in normal mouse skin (left) and quantification of autophagic vacuoles (right). The yellow arrowheads indicate autophagic vacuoles. Scale bars: 5 μm. Mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, #P < 0.05, ##P < 0.01, §§P < 0.01. Statistical significance was determined by 2-tailed Student’s t test. All of the data are representative of 3 independent experiments.