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

Abstract

SummaryEzh2, 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.

Talin1 controls dendritic cell activation by regulating TLR complex assembly and signaling

“…8 H, right). These results are consistent with the findings of earlier reports (Gomez de Agüero et al, 2012;Loh et al, 2018) and confirm the critical role of mLCs in promoting skin tolerance via T reg cell activation in sdLNs. Moreover, our data indicate that (E) Absolute numbers (scatter plots) of ICOS + CD4 + Foxp3 + T reg cells in the sdLNs of Tln1 f/f and Tln1 f/f CD11c-Cre mice 5 d after vehicle painting or DNTB tolerization.…”

Talin1 sets the stage for dendritic cell activation

“…In agreement with this concept, using DC-specific talin1 knockout mice (Tln1 f/f CD11c-Cre mice), Lim et al (2020) find that talin1-deficient LCs accumulate in the epidermis under both steady-state and inflammatory conditions. This result confirms earlier work from the same laboratory demonstrating that the methyltransferase Ezh2 controls LC transmigration across the basement membrane through direct methylation of the adapter molecule talin1, which disrupts its binding to F-actin and thereby functionally enhances the cellular disassembly of focal adhesions (Gunawan et al, 2015;Loh et al, 2018).…”

The functional significance of Talin1 in dendritic cells

“…Besides their role in pathogen clearance, DCs are also involved in the pathologies of skin inflammatory diseases such as contact dermatitis 67,68 . Skin DCs are the main drivers of contact dermatitis 69,70,71,72,73 , however, several factors such as the spatial localization of DCs (LCs reside in the epidermis while dermal DCs reside in the dermis), the availability and penetrance of antigens 70,71,72,73,74 and the type of antigen (hapten or protein) 70,71,72 collectively influences the functional compartmentalization of skin DCs in the pathology of contact dermatitis. Besides the assigned roles of skin DCs in epicutaneous candidiasis, functional redundancy of skin DCs can also be observed in other skin conditions such as the induction of immunological tolerance against self or environmental antigens (e.g.…”

“…Besides the assigned roles of skin DCs in epicutaneous candidiasis, functional redundancy of skin DCs can also be observed in other skin conditions such as the induction of immunological tolerance against self or environmental antigens (e.g. non-allergic hapten 2,4-dinitrothiocyanobenzene (DNTB)), whereby both LCs and dermal DC subsets can promote immunosuppressive or tolerogenic responses via the activation of Foxp3 + regulatory T cells 73,75,76 . The functional role of unique skin DC subsets becomes critical in situations of low or limited antigen exposure.…”

“…Recently, our lab described the significance of talin1 methylation in the integrindependent migration of DC 73,124 and neutrophils 282 , whereby the tri-methylation of talin1…”