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The psoriatic skin resembles wound healing, and it shows abnormalities at the basement membrane (BM), also in the non-lesional skin. Fibroblast-derived dermal periostin has well-known functions in wound healing and Th2-mediated diseases, such as atopic dermatitis. Here we show that serum periostin level was elevated in psoriatic patients, remarkably in the systemically treated ones. Obvious periostin positivity was detected in basal keratinocytes of the non-lesional, lesional, and previously-lesional psoriatic vs. healthy skin. Ex vivo skin models were generated to examine how different skin injuries affect periostin expression during wound healing. Our newly developed cultured salt-split model demonstrated that BM-injury induced periostin expression in basal keratinocytes, and periostin levels in the supernatant were also increased upon healing. In wound healing models, β1-integrin expression was similarly induced. β1-integrin blocking caused reduced periostin expression in in vitro scratch assay, indicating that β1-integrin can mediate periostin production. In contrast to atopic dermatitis, psoriatic basal keratinocytes are in an activated state and show a stable wound healing-like phenotype with the overexpression of periostin. This abnormal BM-induced wound healing as a potential compensatory mechanism can be initiated already in the non-lesional skin present in the lesion and keratinocytes can remain activated in the healed skin. [ABSTRACT FROM AUTHOR]

Introduction Chronic pruritus is a characteristic of atopic dermatitis (AD), contributing to poor quality of life in patients. Alterations in neuroanatomy and neuroarchitecture associated with pruritus secondary to AD are not fully understood. Objectives: To explore the role of dupilumab treatment effect on epidermal neuroanatomy by quantifying intraepidermal nerve fiber density (IENFD). Method DIFFERENSTAD (NCT04823130) was an open-label, exploratory study that enrolled patients = 18 years old with moderate-to-severe AD, pruritus lasting > 6 weeks, and Worst Itch Numerical Rating Scale (WI-NRS) = 4, and matched healthy controls. Patients with AD received dupilumab 300 mg every 2 weeks for 16 weeks. Skin biopsies were obtained from patients' lesional skin at baseline and localization-matched skin at Week 17 (end of treatment, EoT) and from healthy controls. The primary endpoint, IENFD, was defined as number of nerve fibers crossing the basement membrane per millimeter. Results: 31 patients with moderate-to-severe AD and 10 matched controls were enrolled. IENFD in patients with AD significantly increased from baseline to EoT (mean [SE]: 7.7 [1.3] at baseline vs 12.1 [2.0] at EoT for patients with AD; P = 0.0017), to levels comparable with the control group (mean [SE]: 12.4 [2.3]; P for control group vs EoT in patients with AD = 0.9374). Mean (SE) Eczema Area and Severity Index (EASI) total score and WI-NRS in dupilumab-treated patients were 22.5 (1.5) and 8.5 (0.3) at baseline, and 5.1 (1.1) and 3.1 (0.5) at EoT (both change from baseline P < 0.0001), respectively. The safety profile was consistent with the known safety profile for dupilumab. Conclusions: Dupilumab treatment significantly increased IENFD to levels similar to those of healthy subjects, suggesting restored neuroanatomy in patients with moderate-to-severe AD. Dupilumab also significantly improved clinical signs and pruritus symptoms of AD. [ABSTRACT FROM AUTHOR]

In skin, although the extracellular matrix (ECM) is highly developed in dermis and hypodermis, discrete intercellular spaces between cells of the living epidermal layers are also filled with ECM components. Herein, we review knowledge about structure, localization and role of epidermal hyaluronan (HA), a key ECM molecule. HA is a non-sulfated glycosaminoglycan non-covalently bound to proteins or lipids. Components of the basal lamina maintain some segregation between the epidermis and the underlying dermis, and all epidermal HA is locally synthesized and degraded. Functions of HA in keratinocyte proliferation and differentiation are still controversial. However, through interactions with partners, such as the TSG-6 protein, HA is involved in the formation, organization and stabilization of the epidermal ECM. In addition, epidermal HA is involved in the formation of an efficient epidermal barrier made of cornified keratinocytes. In atopic dermatitis (AD) with profuse alterations of the epidermal barrier, HA is produced in larger amounts by keratinocytes than in normal skin. Epidermal HA inside AD lesional skin is located in enlarged intercellular spaces, likely as the result of disease-related modifications of HA metabolism. [ABSTRACT FROM AUTHOR]

Although, drugs are required in the various skin compartments such as viable epidermis, dermis, or hair follicles, to efficiently treat skin diseases, drug delivery into and across the skin is still challenging. An improved understanding of skin barrier physiology is mandatory to optimize drug penetration and permeation. The various barriers of the skin have to be known in detail, which means methods are needed to measure their functionality and outside-in or inside-out passage of molecules through the various barriers. In this review, we summarize our current knowledge about mechanical barriers, i.e., stratum corneum and tight junctions, in interfollicular epidermis, hair follicles and glands. Furthermore, we discuss the barrier properties of the basement membrane and dermal blood vessels. Barrier alterations found in skin of patients with atopic dermatitis are described. Finally, we critically compare the up-to-date applicability of several physical, biochemical and microscopic methods such as transepidermal water loss, impedance spectroscopy, Raman spectroscopy, immunohistochemical stainings, optical coherence microscopy and multiphoton microscopy to distinctly address the different barriers and to measure permeation through these barriers in vitro and in vivo. [ABSTRACT FROM AUTHOR]