Abstract
A functional epithelial barrier necessitates protection against dehydration, and ichthyoses are caused by defects in maintaining the permeability barrier in the stratum corneum (SC), the uppermost protective layer composed of dead cells and secretory materials from the living layer stratum granulosum (SG). We have found that loricrin (LOR) is an essential effector of cornification that occurs in the uppermost layer of SG (SG1). LOR promotes the maturation of corneocytes and extracellular adhesion structure through organizing disulfide cross-linkages, albeit being dispensable for the SC permeability barrier. This review takes psoriasis and AD as the prototype of impaired cornification. Despite exhibiting immunological traits that oppose each other, both conditions share the epidermal differentiation complex as a susceptible locus. We also review recent mechanistic insights on skin diseases, focusing on the Kelch-like erythroid cell-derived protein with the cap “n” collar homology-associated protein 1/NFE2-related factor 2 signaling pathway, as they coordinate the epidermis-intrinsic xenobiotic metabolism. Finally, we refine the theoretical framework of thiol-mediated crosstalk between keratinocytes and leukocytes in the epidermis that was put forward earlier.
Highlights
In the tissue-protective scenario, we have found that small proline-rich proteins (SPRR2) [57] or late cornified envelope proteins (LCE1) [61] are direct downstream targets of the KEAP1/NFE2-related factor 2 (NRF2) signaling pathway
On the or the IL-23 receptorsuccess allele may of immunotherapies targeting the IL-23/IL-17 pathway [69] denotes, inhibiting the rapid represent the immune-driven nature of psoriatic diseases (Online Mendelian Inheritance polymorphological neutrophil influx that occurs in a noncognate fashion [70] (i.e., the in Man (OMIM), accessed on[71])
Mouse studies suggest that a nonsense mutation Y208Stop in transmembrane protein 79 (TMEM79), identified in the “flaky tail” mice [141,142], results in spontaneous skin inflammation that is exaggerated in the BALB/c background [139]
Summary
Cornification is an ultimate form of body wall protection [1], in which molecules are packaged (cross-linked), secreted, and degraded (desquamation). Keratinization is a shared differentiation program among stratified squamous epithelia that cover wet surfaces ( in the hard palate, tongue papilla, or vagina), keratinocytes in the interfollicular epidermis or the follicular infundibulum are exclusively allowed to form the stratum corneum (SC) [2]. The differentiation program of epidermal keratinocytes starts following the exit from the proliferative layer (stratum basale) and detachment from the basement membrane [7]. Microenvironmental cues, such as the calcium gradient [8], vitamin D [9], or vitamin A [10,11], profoundly affect cellular fate. The “leaky” SC further aggravates local inflammatory responses despite the “preemptive” adaptive immunity [41], constituting an integral part of AD’s vicious cycle
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