E-Cadherin is Dispensable to Maintain Langerhans Cells in the Epidermis

Abstract

The cell adhesion molecule E-cadherin is a major component of adherens junctions and marks Langerhans cells (LC), the only dendritic cell (DC) population of the epidermis. LC form a dense network and attach themselves to the surrounding keratinocytes via homophilic E-cadherin binding. LC activation, mobilization, and migration require a reduction in LC E-cadherin expression. To determine whether E-cadherin plays a role in regulating LC homeostasis and function, we generated CD11c-specific E-cadherin knockout mice (CD11c-Ecad del ). In the absence of E-cadherinÀmediated cell adhesion, LC numbers remained stable and similar as in control mice, even in aged animals. Intriguingly, E-cadherinÀdeficient LC displayed a dramatically changed morphology characterized by a more rounded cell body and fewer dendrites than wild-type cells. Nevertheless, maturation and migration of LC lacking E-cadherin was not altered, neither under steady-state nor inflammatory conditions. Accordingly, CD11c-Ecad del and control mice developed comparable contact hypersensitivity reactions and imiquimod-triggered psoriatic skin inflammation, indicating that E-cadherin on LC does not influence their ability to orchestrate T cell-mediated immunity. In conclusion, our data demonstrate that E-cadherin is dispensable to maintain LC in the epidermis and does not regulate LC maturation, migration, and function.

The role of Langerhans cells in epidermal homeostasis and pathogenesis of psoriasis

“…27 After the mature LCs migrate to the epidermis, the hydrophilic E-cadherin binds to the surrounding keratinocytes, which can maintain the stability of LCs in the epidermis. 28 E-cadherin is a transmembrane glycoprotein that mediates Ca2 + -dependent intercellular adhesion. It is the main component of adhesion junction and helps to maintain the integrity of the epidermal barrier.…”

“…However, the absence of E-cadherin did not affect the turnover, maturation, migration and function of LCs, and E-cadherin was down-regulated during LCs mobilization and migration from the epidermis. 28 The non-haematopoietic origin of TGF-β1 is considered to play an important role in promoting LC renewal. 30 In vivo, TGF-β1 is secreted by white blood cells and non-haematopoietic cells (including keratinocytes).…”

“…Although LCs in the epidermis are mainly derived from myeloid progenitor cells, they can exist for a long time after migration to the epidermis and can renew themselves in a steady state 27 . After the mature LCs migrate to the epidermis, the hydrophilic E‐cadherin binds to the surrounding keratinocytes, which can maintain the stability of LCs in the epidermis 28 . E‐cadherin is a transmembrane glycoprotein that mediates Ca2 + ‐dependent intercellular adhesion.…”

“…LCs without E‐cadherin showed significant morphological change: more round cell bodies and fewer dendrites. However, the absence of E‐cadherin did not affect the turnover, maturation, migration and function of LCs, and E‐cadherin was down‐regulated during LCs mobilization and migration from the epidermis 28 . The non‐haematopoietic origin of TGF‐β1 is considered to play an important role in promoting LC renewal 30 .…”

Talin1 sets the stage for dendritic cell activation

“…Intriguingly, Lim et al (2020) observe that talin1-deficient LCs, despite similar surface expression in the steady state, fail to down-regulate Ecadherin upon activation. Although the lack of E-cadherin alone does not trigger EMT and LC emigration from the skin (Brand et al, 2020), conversely, the inability to down-regulate E-cadherin could prevent talin1-deficient LCs to disengage from the keratinocytes and acquire a motile phenotype, contributing to their inability to leave the epidermis. Whether talin1 also influences EMT in a broader sense during LC mobilization remains to be investigated, although the up-regulation of MMP2/9 was not affected by the lack of talin1 (yet insufficient to rescue their inability to cross the basement membrane).…”