Loh JT, Lim TJF, Ikumi K, et al. Ezh2 Controls Skin Tolerance through Distinct Mechanisms in Different Subsets of Skin Dendritic Cells. iScience. 2018;10:23–39. doi:10.1016/j.isci.2018.11.019
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.
We thank H.Y. Lim and V. Angeli for their suggestions on skin imaging, S. Kasuya for technical assistance on
the human skin experiments, and C. Ruedl for critical reading of the manuscript. The study benefitted from
the data assembled by the ImmGen consortium. Dr. Neil McCarthy of Insight Editing London critically reviewed the manuscript. This work was mainly supported by the Ministry of Education Singapore (AcRFTier1-RG40/13, RG36/17, and MOE2013-T2-2-038) and Ministry of Health, National Medical Research
Council (NMRC-CBRG/0057/201) to I.-h.S., and was also funded by Grants-in-Aid for Challenging Exploratory Research (16K15259), Scientific Research B (16H05177) from the Japan Society for the Promotion of
Science, Grant-in-Aid for Scientific Research on Innovative Area (17H05798) from the MEXT, Toyoaki Scholarship Foundation, and Kobayashi International Scholarship Foundation to S.Y. These funding bodies
played no role in the study design, data collection or analysis, the decision to publish, or preparation of