Ezh2 Controls Skin Tolerance through Distinct Mechanisms in Different Subsets of Skin Dendritic Cells

Jia Tong Loh; Thomas Jun Feng Lim; Kyoko Ikumi; Takuma Matoba; Baptiste Janela; Merry Gunawan; Tatsuya Toyama; Maegan Bunjamin; Lai Guan Ng; Michael Poidinger; Akimichi Morita; Florent Ginhoux; Sayuri Yamazaki; Kong-Peng Lam; I-Hsin Su

doi:10.1016/j.isci.2018.11.019

Ezh2 Controls Skin Tolerance through Distinct Mechanisms in Different Subsets of Skin Dendritic Cells

iScience. 2018 Dec 21:10:23-39. doi: 10.1016/j.isci.2018.11.019. Epub 2018 Nov 14.

Authors

Affiliations

¹ School of Biological Sciences, College of Science, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Republic of Singapore; Bioprocessing Technology Institute, Agency for Science, Technology and Research, 20 Biopolis Way, Singapore 138668, Republic of Singapore.
² School of Biological Sciences, College of Science, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Republic of Singapore.
³ Department of Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan; Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
⁴ Department of Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan; Department of Otorhinolaryngology and Head and Neck Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
⁵ Singapore Immunology Network, Agency for Science, Technology and Research, 8A Biomedical Grove, Singapore 138648, Republic of Singapore.
⁶ Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
⁷ Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
⁸ Department of Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
⁹ Bioprocessing Technology Institute, Agency for Science, Technology and Research, 20 Biopolis Way, Singapore 138668, Republic of Singapore.
¹⁰ School of Biological Sciences, College of Science, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Republic of Singapore. Electronic address: ihsu@ntu.edu.sg.

Abstract

Ezh2, a well-established epigenetic repressor, can down-regulate leukocyte inflammatory responses, but its role in cutaneous health remains elusive. Here we demonstrate that Ezh2 controls cutaneous tolerance by regulating Langerhans cell (LC) transmigration across the epidermal basement membrane directly via Talin1 methylation. Ezh2 deficiency impaired disassembly of adhesion structures in LCs, leading to their defective integrin-dependent emigration from the epidermis and failure in tolerance induction. Moreover, mobilization of Ezh2-deficient Langerin^- dermal dendritic cells (dDCs) via high-dose treatment with a weak allergen restored tolerance, which is associated with an increased tolerogenic potential of Langerin^- dDCs likely due to epigenetic de-repression of Aldh in the absence of Ezh2. Our data reveal novel roles for Ezh2 in governing LC- and dDC-mediated host protection against cutaneous allergen via distinct mechanisms.

Keywords: Biological Sciences; Dermatology; Immunology.