Protease activity enhances production of thymic stromal lymphopoietin and basophil accumulation in flaky tail mice

Catharina S. Moniaga, Se Kyoo Jeong, Gyohei Egawa, Saeko Nakajima, Mariko Hara-Chikuma, Jeong Eun Jeon, Seung Hun Lee, Toshihiko Hibino, Yoshiki Miyachi, Kenji Kabashima

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Abstract

Epidermal barrier abnormality due to filaggrin deficiency is an important predisposing factor in the development of atopic dermatitis (AD). In addition, the expression of thymic stromal lymphopoietin (TSLP) in keratinocytes (KCs), induced by barrier disruption, can promote type 2 helper T-cell polarization. Protease activity, including protease-activated receptor-2 (PAR-2), is also known to be involved in epidermal barrier function in AD. However, to our knowledge, the relationship between protease activity and filaggrin deficiency from the perspective of AD has not been elucidated. Flaky tail (Flg ft) mice, known to have a mutation in the filaggrin gene, were used to assess the role of protease in KCs in the steady state and the mite-induced AD-like skin inflammation model. In the steady state, the expression and activity levels of endogenous proteases, kallikreins 5, 7, and 14, in the skin and TSLP were higher in Flgft than in control mice. In addition, activation of PAR-2 by its agonist induced the production of TSLP in KCs of Flgft mice, which was abrogated by a newly developed PAR-2 antagonist. Application of the PAR-2 antagonist improved symptoms and basophil accumulation in Flgft mice treated with mite extracts. These results suggest that possibly through the PAR-2 activation in KCs, filaggrin deficiency induces TSLP production and basophil accumulation, which play important roles in the establishment of AD.

Original languageEnglish
Pages (from-to)841-851
Number of pages11
JournalAmerican Journal of Pathology
Volume182
Issue number3
DOIs
Publication statusPublished - 2013 Mar 1
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Moniaga, C. S., Jeong, S. K., Egawa, G., Nakajima, S., Hara-Chikuma, M., Jeon, J. E., Lee, S. H., Hibino, T., Miyachi, Y., & Kabashima, K. (2013). Protease activity enhances production of thymic stromal lymphopoietin and basophil accumulation in flaky tail mice. American Journal of Pathology, 182(3), 841-851. https://doi.org/10.1016/j.ajpath.2012.11.039