Endoplasmic Reticulum Calcium Regulates Epidermal Barrier Response and Desmosomal Structure

Abstract

Ca2+ fluxes direct keratinocyte differentiation, cell-to-cell adhesion, migration, and epidermal barrier homeostasis. We previously showed that intracellular Ca2+ stores constitute a major portion of the calcium gradient especially in the stratum granulosum. Loss of the calcium gradient triggers epidermal barrier homeostatic responses. In this report, using unfixed ex vivo epidermis and human epidermal equivalents we show that endoplasmic reticulum (ER) Ca2+ is released in response to barrier perturbation, and that this release constitutes the major shift in epidermal Ca2+ seen after barrier perturbation. We find that ER Ca2+ release correlates with a transient increase in extracellular Ca2+. Lastly, we show that ER calcium release resulting from barrier perturbation triggers transient desmosomal remodeling, seen as an increase in extracellular space and a loss of the desmosomal intercellular midline. Topical application of thapsigargin, which inhibits the ER Ca2+ ATPase activity without compromising barrier integrity, also leads to desmosomal remodeling and loss of the midline structure. These experiments establish the ER Ca2+ store as a master regulator of the Ca2+ gradient response to epidermal barrier perturbation, and suggest that ER Ca2+ homeostasis also modulates normal desmosomal reorganization, both at rest and after acute barrier perturbation.

Transient elevation of cytoplasmic calcium ion concentration at a single cell level precedes morphological changes of epidermal keratinocytes during cornification

“…Although the causal relationship between the elevation of [Ca 2+ ] i and cornification was not evaluated in this study, our data strongly suggest that the transient elevation of [Ca 2+ ] i is involved in the mechanisms of cornification. Indeed, previous studies demonstrated rapid increase in the number of transitional cells after elevation of [Ca 2+ ] i by an inhibition of sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA) 12 , 32 . Furthermore, it is known that Ca 2+ is required to activate the transglutaminases that assemble the cornified envelope, a protective barrier structure inside the plasma membrane 33 .…”

H19 lncRNA regulates keratinocyte differentiation by targeting miR-130b-3p

“…H19 decreases the activity of miR-130b-3p and consequently increases the expression of miR-130b-3p downstream target Dsg1. Calcium stimulation, which may come from endoplasmic reticulum (ER) Ca 2+ release in response to barrier perturbation under pathological conditions, 37 leads to a significant upregulation of H19 and therefore competes with coding mRNA Dsg1 for miR-130b-3p and relieves the inhibitory effect of miR-130b-3p on Dsg1, thereby leading to increased Dsg1 expression, which promotes keratinocyte differentiation. Furthermore, the downregulation of H19 in psoriasis tissues compared with normal tissues was observed in lncRNA profiling studies.…”

Primary role of barrier dysfunction in the pathogenesis of atopic dermatitis

“…Thus, despite underlying abnormalities in corneocyte proteins, accelerated paracellular water loss accounts for the permeability barrier abnormality in AD . While decreased expression of certain tight junction proteins has also been demonstrated in both IV and AD, these partially formed structures do not provide a barrier to the paracellular movement of water across normal adult epidermis . Nonetheless, loss of residual TJ proteins could allow accelerated ingress of antigens and microbial pathogens across the SC in AD.…”