The Immunological Impact of IL-1 Family Cytokines on the Epidermal Barrier

The skin barrier would not function without IL-1 family members, but their physiological role in the immunological aspects of skin barrier function are often overlooked. This review summarises the role of IL-1 family cytokines (IL-1α, IL-1β, IL-1Ra, IL-18, IL-33, IL-36α, IL-36β, IL-36γ, IL-36Ra, IL-37 and IL-38) in the skin. We focus on novel aspects of their interaction with commensals and pathogens, the important impact of proteases on cytokine activity, on healing responses and inflammation limiting mechanisms. We discuss IL-1 family cytokines in the context of IL-4/IL-13 and IL-23/IL-17 axis-driven diseases and highlight consequences of human loss/gain of function mutations in activating or inhibitory pathway molecules. This review highlights recent findings that emphasize the importance of IL-1 family cytokines in both physiological and pathological cutaneous inflammation and emergent translational therapeutics that are helping further elucidate these cytokines.

An altered skin microbiome is the most important symptom of atopic dermatitis.

Fast traslate Icon translate Fast traslate Icon translate The progressive increase in the incidence of atopic dermatitis among children, an increase in persistence in adulthood, combined with an inevitable decrease in the quality of life of patients, determine the relevance of studying the mechanisms of the development of this disease not only for dermatology, but also for the entire health care system. Thus, the prerequisites for the emergence of new concepts of pathogenesis and the search for the most effective therapeutic modalities arise. At the moment, atopic dermatitis is considered as the interaction of endogenous (impaired immune response, insufficient function of the epidermal barrier) and exogenous (exposure to allergens, chemical or physical irritants, microorganisms) factors. Environmental factors such as temperature and humidity, genetic makeup, antibiotic use, and good hygiene play a critical role in the maintenance and stability of the skin microbiome. Normally, the skin microbiota is mainly formed by bacteria of the genus Staphylococcus, Propionibacterium, Corynebacterium and Streptococcus. While in patients with AD, in 70% of cases, there is colonization of Staphylococcus aureus on the affected skin, in 39% on intact skin, which secondarily contributes to the development of immune imbalance and increased skin xerosis. This fact determines the importance of the use of basic therapy, which, on the one hand, helps to strengthen the epidermal barrier, and on the other hand, normalizes the microbiome of the skin, reducing the colonization of Staphylococcus aureus.

Transdermal Drug Delivery in the Pig Skin

Transdermal delivery can be accomplished through various mechanisms including formulation optimization, epidermal stratum corneum barrier disruption, or directly by removing the stratum corneum layer. Microneedling, electroporation, a combination of both and also the intradermal injection known as mesotherapy have proved efficacy in epidermal-barrier disruption. Here we analyzed the effects of these methods of epidermal-barrier disruption in the structure of the skin and the absorption of four compounds with different characteristics and properties (ketoprofen, biotin, caffein, and procaine). Swine skin (Pietrain x Durox) was used as a human analogue, both having similar structure and pharmacological release. They were biopsied at different intervals, up to 2 weeks after application. High-pressure liquid chromatography and brightfield microscopy were performed, conducting a biometric analysis and measuring histological structure and vascular status. The performed experiments led to different results in the function of the studied molecules: ketoprofen and biotin had the best concentrations with intradermal injections, while delivery methods for obtaining procaine and caffein maximum concentrations changed on the basis of the lapsed time. The studied techniques did not produce significant histological alterations after their application, except for an observed increase in Langerhans cells and melanocytes after applying electroporation, and an epidermal thinning after using microneedles, with variable results regarding dermal thickness. Although all the studied barrier disruptors can accomplish transdermal delivery, the best disruptor is dependent on the particular molecule.

Epidermal Hyaluronan in Barrier Alteration-Related Disease

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.

Filaggrin and Atopic Dermatitis: Clinical and Pathogenetic Parallels and Therapeutic Possibilities

Atopic dermatitis (AtD) is multifactorial inflammatory skin disease, one of the aspects of its pathogenesis is epidermal barrier dysfunction. Early development of AtD is associated with filaggrin dysfunction. Filaggrin is a protein involved in aggregation of keratin filaments in the upper layers of epidermis and the retention of lipids and proteins between corneocytes. Frequently, filaggrin dysfunction can be accompanied with secondary infection and high risk of other allergic diseases development. This can happen due to disturbance in terminal differentiation of epidermal cells and, as consequence, malfunction of epidermal barrier. Thus, the long regular use of emollients is the basis of AtD therapy. New class of emollients (“emollents plus”) allowed us to achieve more significant treatment results in patients with AtD. These emollients reduce inflammatory process activity in the skin by replacing structural components of abnormal epidermal barrier.

Continuous ZnO nanoparticle exposure induces melanoma-like skin lesions in epidermal barrier dysfunction model mice through anti-apoptotic effects mediated by the oxidative stress–activated NF-κB pathway

Background: Increasing interest in the hazardous properties of zinc oxide nanoparticles (ZnO NPs), commonly used as ultraviolet filters in sunscreen, has driven efforts to study the percutaneous application of ZnO NPs to diseased skin; however, in-depth studies of toxic effects on melanocytes under conditions of epidermal barrier dysfunction remain lacking. Methods: Epidermal barrier dysfunction model mice were continuously exposed to a ZnO NP-containing suspension for up to 14 and even 49 days in vivo. Melanoma-like change and molecular mechanisms were also verified in human epidermal melanocytes treated with 5.0 µg·mL −1 ZnO NPs for 72 h in vitro. Results: ZnO NP application for 14 and 49 consecutive days induced melanoma-like skin lesions, dysregulated melanoma-associated gene expression, increased oxidative injury, inhibited apoptosis, and increased nuclear factor kappa B (NF-κB) p65 and Bcl-2 expression in melanocytes of skin with epidermal barrier dysfunction. Exposure to 5.0 µg·mL −1 ZnO NPs for 72 h increased cell viability, decreased apoptosis, and increased Fkbp51 expression in melanocytes, consistent with histological observations. The oxidative stress–mediated mechanism underlying the induction of anti-apoptotic effects was verified using the reactive oxygen species scavenger N-acetylcysteine. Conclusions: The entry of ZnO NPs into the stratum basale of skin with epidermal barrier dysfunction resulted in melanoma-like skin lesions and an anti-apoptotic effect induced by oxidative stress, activating the NF-κB pathway in melanocytes.

Epidermal Barrier Dysfunction in Atopic Dermatitis

Impaired skin barrier is one of the hallmarks of atopic dermatitis (AD), with abnormalities in the cornified envelope, lipid lamellae, tight junctions and cutaneous microbiome. These findings are also present in nonlesional skin of AD individuals, suggesting that epidermal barrier defects may be the initial step towards the development of AD and eventually other atopic diseases (atopic march). It is currently known that pathophysiology of AD involves an interplay between this dysfunctional skin barrier and a predominantly type 2 skewed innate and adaptive immune responses, which further disrupt the skin barrier through type 2 cytokines. In this setting, there is enhanced penetration of environmental and food allergens through a deficient barrier, leading to an increased susceptibility to sensitization. During the sensitization process, thymic stromal lymphopoietin (TSLP) polarizes skin dendritic cells to a T-helper 2 response, and TSLP seems to be a key cytokine in the sensitization of food allergy, allergic asthma and rhinitis. In this review, the authors describe the current knowledge of the pathophysiology of the epidermal barrier, its disruption in AD and how it may be involved in the development of atopic comorbidities and the role of barrier repair therapy on the prevention of the atopic march progression.