Human β-defensin-3 attenuates atopic dermatitis–like inflammation through autophagy activation and the aryl hydrocarbon receptor signaling pathway
Ge Peng, … , Shigaku Ikeda, François Niyonsaba
Ge Peng, … , Shigaku Ikeda, François Niyonsaba
Published July 14, 2022
Citation Information: J Clin Invest. 2022;132(17):e156501. https://doi.org/10.1172/JCI156501.
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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 2

Th2-derived cytokines are involved in the inactivation of autophagy in AD keratinocytes.

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Th2-derived cytokines are involved in the inactivation of autophagy in A...
(A–C) Keratinocytes were stimulated for 12 hours with 100 ng/mL IL-4 or IL-13 alone or in combination in the presence (+) or absence (–) of 10 μg/mL E&P; n = 3 per group. Representative p62 and LC3 immunoblots (left) and quantification of band intensities (right). GAPDH was used as a loading control. (D) Keratinocytes were stimulated for 12 hours with or without IL-4 or IL-13 alone or in combination in the presence of 10 μM rapamycin (Rap); n = 5 per group. Representative immunofluorescence images (left) and quantification of LC3 puncta in keratinocytes (right). Scale bars: 10 μm. Mean ± SD. *P < 0.05, **P < 0.01, ****P < 0.0001, #P < 0.05, ###P < 0.001, ####P < 0.0001. Statistical significance was determined by 2-tailed Student’s t test or 1-way ANOVA with Tukey’s multiple-comparison test. All of the data are representative of 3 independent experiments.