Retinoids Reduce Formation of Keratin Aggregates in Heat-stressed Immortalized Keratinocytes from an Epidermolytic Ichthyosis Patient with a KRT10 Mutation*

Abstract

Epidermolytic ichthyosis (EI) is an autosomal dominant epidermal skin fragility disorder caused by mutations in keratin 1 and 10 (K1 and K10) genes. Mutated keratins form characteristic aggregates in vivo and in vitro. Some patients benefit from retinoid therapy, although the mechanism is not fully understood. Our aim was to demonstrate whether retinoids affect the formation of keratin aggregates in immortalized EI cells in vitro. EI keratinocytes were seeded on cover slips, pre-treated or not with retinoids, heat-stressed, and keratin aggregate formation monitored. K10 aggregates were detected in 5% of cells in the resting state, whereas heat stress increased this proportion to 25%. When cells were pre-incubated with all-trans-retinoic acid (ATRA) or retinoic acid receptor (RAR)-α agonists the aggregates decreased in a dose-dependent manner. Furthermore, ATRA decreased the KRT10 transcripts 200-fold as well as diminished the ratio of mutant to wild-type transcripts from 0.41 to 0.35, thus providing a plausible rational for retinoid therapy of EI due to K10 mutations.

Mutations Affecting Keratin 10 Surface-Exposed Residues Highlight the Structural Basis of Phenotypic Variation in Epidermolytic Ichthyosis

“…Apart from architectural support, keratins have a crucial role in keratinocyte differentiation, growth, and proliferation (Santos et al, 2002;Paramio et al, 2007). Disruption of these non-structural functions due to mislocalization (Choate et al, 2010) or gain of potentially toxic functions by aggregation (Li and Törmä, 2013) may determine clinical outcomes of specific keratin mutations. Rod domain mutations found in severe EI show accumulation of cytotoxic keratin aggregates in suprabasal keratinocytes, epidermolysis, disrupted epidermal differentiation, and basal cell hyperproliferation (Fuchs et al, 1994).…”

Physiological Doses of Red Light Induce IL‐4 Release in Cocultures between Human Keratinocytes and Immune Cells

“…Keratin 10 aggregation has been reported in keratinocytes under conditions of cell stress . KRT10 immunostaining appeared normal in both control‐ and single dose‐treated keratinocytes during early differentiation (i.e.…”

Neuroendocrine Controls of Keratin Expression in Human Skin

“…It has also been reported to be of potential benefit in epidermolytic ichthyosis, an uncommon genodermatosis caused by mutations in keratins 1 or 10, when Reichelt et al have shown that increased stability of keratins 5 and 14 could lead to the formation of normal epidermis in K10-null mice [97]. Furthermore, treatment of immortalized cell lines from a KRT10-mutated epidermolytic ichthyosis patient with all-trans retinoic acid led to a 200-fold decrease in mRNA expression of K10, accompanied by decreased keratin aggregation [98].…”