Y Mitamura1,2, S Nunomura1, Y Nanri1, M Ogawa1, T Yoshihara1, M Masuoka1, G Tsuji2, T Nakahara2, A Hashimoto-Hachiya2, S J Conway3, M Furue2, K Izuhara1. 1. Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga, Japan. 2. Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 3. HB Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
Abstract
BACKGROUND: Barrier dysfunction is an important feature of atopic dermatitis (AD) in which IL-4 and IL-13, signature type 2 cytokines, are involved. Periostin, a matricellular protein induced by IL-4 or IL-13, plays a crucial role in the onset of allergic skin inflammation, including barrier dysfunction. However, it remains elusive how periostin causes barrier dysfunction downstream of the IL-13 signal. METHODS: We systematically identified periostin-dependent expression profile using DNA microarrays. We then investigated whether IL-24 downregulates filaggrin expression downstream of the IL-13 signals and whether IL-13-induced IL-24 expression and IL-24-induced downregulation of filaggrin expression are dependent on the JAK/STAT pathway. To build on the significance of in vitro findings, we investigated expression of IL-24 and activation of STAT3 in mite-treated mice and in AD patients. RESULTS: We identified IL-24 as an IL-13-induced molecule in a periostin-dependent manner. Keratinocytes are the main IL-24-producing tissue-resident cells stimulated by IL-13 in a periostin-dependent manner via STAT6. IL-24 significantly downregulated filaggrin expression via STAT3, contributing to barrier dysfunction downstream of the IL-13/periostin pathway. Wild-type mite-treated mice showed significantly enhanced expression of IL-24 and activation of STAT3 in the epidermis, which disappeared in both STAT6-deficient and periostin-deficient mice, suggesting that these events are downstream of both STAT6 and periostin. Moreover, IL-24 expression was enhanced in the epidermis of skin tissues taken from AD patients. CONCLUSIONS: The IL-13/periostin pathway induces IL-24 production in keratinocytes, playing an important role in barrier dysfunction in AD.
BACKGROUND: Barrier dysfunction is an important feature of atopic dermatitis (AD) in which IL-4 and IL-13, signature type 2 cytokines, are involved. Periostin, a matricellular protein induced by IL-4 or IL-13, plays a crucial role in the onset of allergic skin inflammation, including barrier dysfunction. However, it remains elusive how periostin causes barrier dysfunction downstream of the IL-13 signal. METHODS: We systematically identified periostin-dependent expression profile using DNA microarrays. We then investigated whether IL-24 downregulates filaggrin expression downstream of the IL-13 signals and whether IL-13-induced IL-24 expression and IL-24-induced downregulation of filaggrin expression are dependent on the JAK/STAT pathway. To build on the significance of in vitro findings, we investigated expression of IL-24 and activation of STAT3 in mite-treated mice and in ADpatients. RESULTS: We identified IL-24 as an IL-13-induced molecule in a periostin-dependent manner. Keratinocytes are the main IL-24-producing tissue-resident cells stimulated by IL-13 in a periostin-dependent manner via STAT6. IL-24 significantly downregulated filaggrin expression via STAT3, contributing to barrier dysfunction downstream of the IL-13/periostin pathway. Wild-type mite-treated mice showed significantly enhanced expression of IL-24 and activation of STAT3 in the epidermis, which disappeared in both STAT6-deficient and periostin-deficient mice, suggesting that these events are downstream of both STAT6 and periostin. Moreover, IL-24 expression was enhanced in the epidermis of skin tissues taken from ADpatients. CONCLUSIONS: The IL-13/periostin pathway induces IL-24 production in keratinocytes, playing an important role in barrier dysfunction in AD.
Authors: Matthew G Brewer; Takeshi Yoshida; Fiona I Kuo; Sade Fridy; Lisa A Beck; Anna De Benedetto Journal: Int J Mol Sci Date: 2019-08-21 Impact factor: 5.923
Authors: Alessandra Vultaggio; Ioana Agache; Cezmi A Akdis; Mubeccel Akdis; Sevim Bavbek; Apostolos Bossios; Jean Bousquet; Onur Boyman; Adam M Chaker; Susan Chan; Alexia Chatzipetrou; Wojciech Feleszko; Davide Firinu; Marek Jutel; Paula Kauppi; Ludger Klimek; Antonios Kolios; Akash Kothari; Marek L Kowalski; Andrea Matucci; Oscar Palomares; Oliver Pfaar; Barbara Rogala; Eva Untersmayr; Thomas Eiwegger Journal: Allergy Date: 2020-11 Impact factor: 14.710