Atopic dermatitis (AD) is the most common inflammatory skin disease in the industrialized world and has multiple causes. Over the past decade, data from both experimental models and patients have ...highlighted the primary pathogenic role of skin barrier deficiency in patients with AD. Increased access of environmental agents into the skin results in chronic inflammation and contributes to the systemic “atopic (allergic) march.” In addition, persistent skin inflammation further attenuates skin barrier function, resulting in a positive feedback loop between the skin epithelium and the immune system that drives pathology. Understanding the mechanisms of skin barrier maintenance is essential for improving management of AD and limiting downstream atopic manifestations. In this article we review the latest developments in our understanding of the pathomechanisms of skin barrier deficiency, with a particular focus on the formation of the stratum corneum, the outermost layer of the skin, which contributes significantly to skin barrier function.
Barrier dysfunction in the skin allergy Egawa, Gyohei; Kabashima, Kenji
Allergology International,
January 2018, 20180101, 2018-Jan, 2018-01-00, 2018-01-01, Letnik:
67, Številka:
1
Journal Article
Recenzirano
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The skin is continuously exposed to external pathogens, and its barrier function is critical for skin homeostasis. Previous studies have shown that the barrier dysfunction is one of the most ...predisposing factors for the development of skin allergic diseases such as atopic dermatitis. In this article, we summarize how the physical barrier of the skin is organized and review its link to the pathomechanism of skin allergic diseases. We describe the formation of the SC barrier in terms of the following five categories: 1) filaggrin metabolism; 2) cornified envelope; 3) intercellular lipids; 4) corneodesmosome; and 5) corneocyte desquamation. New approaches to restoring the skin barrier function are also discussed.
Allergic contact dermatitis (ACD) is one of the most common skin diseases, consisting of sensitization and elicitation phases. With the advancement of technology and the discovery of new types of ...immune cells, our knowledge of the immunological mechanisms of contact hypersensitivity (CHS) as a murine model of ACD has expanded significantly in the past decade. For example, by introducing regulatory T cells, CD4+ T-helper 17 cells, and Langerin-positive dermal dendritic cells, the initiation and termination mechanism of CHS has been revealed. In addition, the role of mast cells in CHS, long a matter of debate, has become apparent by developing conditional mast cell–deficient mice. Moreover, the role of the innate immunity system, such as that of Toll-like receptor signaling, has made a breakthrough in this field. In this review, we will integrate the recent advancement of immunological mechanisms of both the sensitization and elicitation phases of CHS into the classic view, and we will discuss updated mechanisms on its development and future directions.
For the induction of adequate cutaneous immune responses, the antigen presentation and recognition that occur in both the skin and skin-draining lymph nodes are essential. In each process of ...cutaneous immune responses, several distinct subsets of immune cells, including dendritic cells and T cells, are involved, and they elicit their respective functions in a harmonious manner. For example, in the elicitation phase of cutaneous acquired immunity, immune cells form a specific lymphoid structure named inducible skin-associated lymphoid tissue (iSALT) to facilitate efficient antigen presentation in situ. In this short review, we will overview the mechanisms of how antigens are presented and how cutaneous adaptive immune responses are conducted in the skin, especially focusing on contact hypersensitivity, a prototypic adaptive immune response in the skin.
Antigen presentation to T cells is essential for the induction of adaptive immunity. This event takes place not solely in the lymph node (LN) but also in the skin. Recent in vivo trafficking studies ...using Kaede-transgenic mice reveal that skin-homing effector memory T cells alter their effector function and homing ability by transitioning to a central memory T cell-like phenotype through antigen recognition that occurs in the skin. In addition, these cells travel back and forth between the skin and draining LNs. These studies are evocative of the classic concept of skin-associated lymphoid tissues and underscore the critical role of skin as a peripheral lymphoid organ.
Mast cells (MCs) are immune cells residing in tissues and playing indispensable roles in maintaining homeostasis and inflammatory states. Skin lesions associated with atopic dermatitis (AD) and type ...2 skin inflammation display an increment in MCs, which have both pro‐ and anti‐inflammatory effects. The direct and indirect activations of skin MCs by environmental factors such as Staphylococcus aureus can instigate type 2 skin inflammation in AD with poorly understood mechanisms. Furthermore, both IgE‐dependent and ‐independent degranulation of MCs contribute to pruritus in AD. Conversely, MCs suppress type 2 skin inflammation by promoting Treg expansion through IL‐2 secretion in the spleen. Moreover, skin MCs can upregulate gene expression involved in skin barrier function, thus mitigating AD‐like inflammation. These functional variances of MCs in AD could stem from differences in experimental systems, their localization, and origins. In this review, we will focus on how MCs are maintained in the skin under homeostatic and inflammatory conditions, and how they are involved in the pathogenesis of type 2 skin inflammation.
Mast cells exhibit pro‐ and anti‐inflammatory effects in atopic dermatitis, type 2 skin inflammation. These functional differences may arise from different experimental systems, their localization, and their origins.
Background Barrier disruption and the resulting continuous exposure to allergens are presumed to be responsible for the development of atopic dermatitis (AD). However, the mechanism through which ...skin barrier function is disrupted in patients with AD remains unclear. Objectives Taking into account the fact that the TH 2 milieu impairs keratinocyte terminal differentiation, we sought to clarify our hypothesis that the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway plays a critical role in skin barrier function and can be a therapeutic target for AD. Methods We analyzed the mechanism of keratinocyte differentiation using a microarray and small interfering RNA targeting STATs. We studied the effect of the JAK inhibitor JTE-052 on keratinocyte differentiation using the human skin equivalent model and normal human epidermal keratinocytes. We applied topical JAK inhibitor onto NC/Nga mice, dry skin model mice, and human skin grafted to immunocompromised mice. Results IL-4 and IL-13 downregulated genes involved in keratinocyte differentiation. STAT3 and STAT6 are involved in keratinocyte differentiation and chemokine production by keratinocytes, respectively. Topical application of the JAK inhibitor suppressed STAT3 activation and improved skin barrier function, permitting increases in levels of terminal differentiation proteins, such as filaggrin, and natural moisturizing factors in models of AD and dry skin and in human skin. Conclusion STAT3 signaling is a key element that regulates keratinocyte differentiation. The JAK inhibitor can be a new therapeutic tool for the treatment of disrupted barrier function in patients with AD.
The identity of Langerhans cells (LCs) has been called into question of late due to the increasing evidence that LCs originate from macrophage lineage instead of dendritic cell (DC) lineage as ...previously thought. For many years, LCs have been assumed to be DCs due to its migratory capabilities. However, recent studies have demonstrated that LCs are from macrophage lineage of the adult fetal liver (FL) progenitor.
LCs are now considered tissue-resident macrophages as they originate from the FL as shown by fate mapping models. In recent years, studies have shown that there are three types of antigen-presenting cells present in the epidermis, such as LCs, monocyte-derived LC-like cells, and inflammatory dendritic epidermal cells (IDECs). Of these, LC-like cells have been characterized in both human and mouse studies, while IDECs have only been described in human studies. This has shed a new light on the area of epidermal macrophages, suggesting that there might be a misidentification and misclassification of LCs. IDECs and LC-like cells have been shown to be present in both steady state and inflammatory state, but they are present in more significant amounts under inflammatory conditions such as atopic dermatitis, ultra violet injury, and psoriasis. In this review, we discuss what is already known and discuss the possible roles of LCs, LC-like cells, and IDECs during inflammation. Most intriguingly, we discuss the possibility of LCs having a dual identity as both a macrophage and a DC. This is shown as LCs are the only tissue-resident macrophage to have shown migratory property-like DCs.
Innate lymphoid cells (ILCs) harbor tissue-resident properties in border zones, such as the mucosal membranes and the skin. ILCs exert a wide range of biological functions, including inflammatory ...response, maintenance of tissue homeostasis, and metabolism. Since its discovery, tremendous effort has been made to clarify the nature of ILCs, and scientific progress revealed that progenitor cells of ILC can produce ILC subsets that are functionally reminiscent of T-cell subsets such as Th1, Th2, and Th17. Thus, now it comes to the notion that ILC progenitors are considered an innate version of naïve T cells. Another important discovery was that ILC progenitors in the different tissues undergo different modes of differentiation pathways. Furthermore, during the embryonic phase, progenitor cells in different developmental chronologies give rise to the unique spectra of immune cells and cause a wave to replenish the immune cells in tissues. This observation leads to the concept of layered immunity, which explains the ontology of some cell populations, such as B-1a cells, γδ T cells, and tissue-resident macrophages. Thus, recent reports in ILC biology posed a possibility that the concept of layered immunity might disentangle the complexity of ILC heterogeneity. In this review, we compare ILC ontogeny in the bone marrow with those of embryonic tissues, such as the fetal liver and embryonic thymus, to disentangle ILC heterogeneity in light of layered immunity.
Regulation of blood vessel permeability is essential for the homeostasis of peripheral tissues. This regulation controls the trafficking of plasma contents, including water, vitamins, ions, hormones, ...cytokines, amyloids, lipoproteins, carrier proteins, and immunoglobulins. The properties of blood vessels vary among tissues based on their structural differences: continuous, fenestrated, or sinusoidal. These three types of blood vessels have different charge and size barrier properties. The anionic luminal glycocalyx layer on endothelial cells establishes the "charge barrier" that repels the attachment of negatively charged blood cells and plasma molecules. In contrast, the "size barrier" of blood vessels largely relies on the interendothelial junctions (IEJs) between endothelial cells, which define the paracellular permeability. As in most peripheral tissues, blood capillaries in the skin are composed of continuous and/or fenestrated blood vessels that have relatively tighter IEJs compared to those in the internal organs. Small vesicles in the capillary endothelium were discovered in the 1950s, and studies have since confirmed that blood endothelial cells transport the plasma contents by endocytosis and subsequent transcytosis and exocytosis-this process is called transcellular permeability. The permeability of blood vessels is highly variable as a result of intrinsic and extrinsic factors. It is significantly elevated upon tissue inflammations as a result of disabled IEJs and increased paracellular permeability due to inflammatory mediators. An increase in transcellular permeability during inflammation has also been postulated. Here, we provide an overview of the general properties of vascular permeability based on our recent observations of murine skin inflammation models, and we discuss its physiological significance in peripheral homeostasis.
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