New concept of the pathogenesis of atopic dermatitis: Interplay among the barrier, allergy, and pruritus as a trinity

doi:10.1016/j.jdermsci.2013.02.001

Journal of Dermatological Science

Volume 70, Issue 1, April 2013, Pages 3-11

https://doi.org/10.1016/j.jdermsci.2013.02.001 Get rights and content

Abstract

Atopic dermatitis (AD) is a common skin condition, characterized by a complex, heterogeneous pathogenesis, including skin barrier dysfunctions, allergy/immunology, and pruritus. When the skin barrier is disrupted by, for example, the filaggrin gene mutation and/or environmental factors, the skin is predisposed to being penetrated by external stimuli. Foreign antigens can be subdivided into two subsets by size: haptens (including metals) and protein antigens. It is known that a single hapten challenge provokes Th1 initially, but that repeated elicitation with haptens results in a shift toward Th2-dominated responses. On the other hand, exposure to protein antigens directly induces Th2-dominant conditions via the thymic stromal lymphopoietin (TSLP) receptor on Langerhans cells. Recently, it has been revealed that Th2 cells produce IL-31, which provokes pruritus, and that Th2 cytokines decrease filaggrin expressions by keratinocytes. These findings suggest that Th2 conditions lead to pruritus and barrier dysfunctions. In this review, we will examine the highly complex interplay among skin barrier abnormality, allergy/immunology, and pruritus as a trinity in the development of AD.

Introduction

Atopic dermatitis (AD) is a relapsing chronic inflammatory skin disease characterized by eczematous skin lesions and intense pruritus [1]. AD is one of the most frequent chronic inflammatory skin diseases and its prevalence is increasing, affecting at least 15% of children and 2–10% of adults in industrialized countries [2]. Patients with AD often have other allergic diseases, including food allergies, asthma, and allergic rhinitis [2]; these often begin early in life and progress in a typical fashion—this is called the allergic (or atopic) march [3]. The skin is an active immune system organ that influences systemic immunity [4].

AD can be categorized into two types: extrinsic or intrinsic. Extrinsic or allergic AD exhibits high total serum IgE levels and the presence of specific IgE for environmental and food allergens, whereas intrinsic or non-allergic AD exhibits normal total IgE values and the absence of specific IgE without filaggrin gene mutations [5]. The skin barrier is perturbed in the extrinsic, but not intrinsic type. The pathogenesis of AD has been attributed to a complex interaction of the environment and host susceptibility genes, altered skin barrier function, the immune system, and pruritus [6], [7]. Thus far, each component has been studied independently; however, recent findings have suggested that they interact in a highly complex manner in the development of AD. In this review, we focus on the role of barrier functions, immune systems, and pruritus in AD, and we discuss their interplay in the development of AD.

Section snippets

Stratum corneum and tight junction

Outermost barriers are critical to avoid desiccation and to protect against foreign insults. Mammalian skin consists of two sets of barriers: stratum corneum and tight junctions (TJs). Thus far, at least four causes of xerosis have been considered: (1) decrease in skin ceramides [8], (ii) alterations of the stratum corneum pH [9], (iii) overexpression of the proteases, including kallikreins (KLKs) and chymases [10], and (iv) defect in Filaggrin (FLG) [11] (Fig. 1).

In Netherton syndrome,

Allergy/immunology

Human AD can be categorized into two types: extrinsic and intrinsic [5] (Table 1). Extrinsic or allergic AD exhibits a high total serum IgE levels and the presence of specific IgE for environmental and food allergens, whereas intrinsic or non-allergic AD exhibits normal total IgE values and the absence of specific IgE [5]. The skin barrier is perturbed in the extrinsic type, which increases the pre-existing pruritus, but not in the intrinsic type. FLG gene mutations are a feature of extrinsic,

Pruritus

Itching, or pruritus, is defined as an unpleasant cutaneous sensation that serves as a physiological self-protective mechanism to prevent the body from being hurt by harmful external agents. Chronic itch represents a significant clinical problem resulting from renal diseases and liver diseases, as well as several serious skin diseases, including AD. The gastrin-releasing peptide receptor or Mrgprs mediates itch sensation in the dorsal spinal cord/C-fiber [86], [87].

Pruritus is known to be

Future direction

In this article, the roles of three important elements in AD: barrier, allergy/immunology, and pruritus, were reviewed independently. The interplay between each factor was then discussed, as illustrated in Fig. 7. These interactions are important in understanding the pathomechanism of AD because they are linked to each other as a trinity. Therefore, in the development of AD, barrier dysfunction, allergy/immunological dysregulation, and pruritus create a positive feedback loop through a highly

Funding

This work was supported in part by Grants-in-Aid for Scientific Research from the Ministries of Education, Culture, Sports, Science and Technology.

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Atopic dermatitis (AD) is a heterogeneous, chronic, relapsing, inflammatory skin disease associated with considerable physical, psychological, and economic burden. The pathology of AD includes complex interactions involving abnormalities in immune and skin barrier genes, skin barrier disruption, immune dysregulation, microbiome disturbance, and other environmental factors. Many of the cytokines involved in AD pathology, including IL-4, IL-13, IL-22, IL-31, thymic stromal lymphopoietin, and IFN-γ, signal through the Janus kinase (JAK)–signal transducer and activation of transcription (STAT) pathway. The JAK family includes JAK1, JAK2, JAK3, and tyrosine kinase 2; the STAT family includes STAT1, STAT2, STAT3, STAT4, STAT5A/B, and STAT6. Activation of the JAK-STAT pathway has been implicated in the pathology of several immune-mediated inflammatory diseases, including AD. However, the exact mechanisms of JAK-STAT involvement in AD have not been fully characterized. This review aims to discuss current knowledge about the role of the JAK-STAT signaling pathway and, specifically, the role of JAK1 in the pathology and symptomology of AD.
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Macroautophagy/autophagy plays a pivotal role in immune regulation. Its significance is evident in modulation of immune cell differentiation and maturation, physiologically and pathologically. Here, we investigate the role of macrophage autophagy on the development of atopic dermatitis (AD). By employing an MC903-induced AD mice model, we observe reduced cutaneous inflammation in macrophage Atg5 cKO mice compared with WT mice. Notably, there is a decreased infiltration of M2 macrophages in lesional skin from Atg5 cKO mice. Furthermore, impaired STAT6 phosphorylation and diminished expression of M2 markers are detected in autophagy-deficient macrophages. Our mechanistic exploration reveals that CEBPB drives the transcription of SOCS1/3 and SQSTM1/p62-mediated autophagy degrades CEBPB normally. Autophagy deficiency leads to CEBPB accumulation, and further promotes the expression of SOCS1/3. This process inhibits JAK1-STAT6 pathway activation and M2 marker expression. Together, our study indicates that autophagy is required for M2 activation and macrophage autophagy may be a promising target for AD intervention.
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Kenji Kabashima received the MD from Kyoto University in 1996. After the internship at the United State Naval Hospital in Yokosuka, Japan, and residency at University of Washington, USA, he received the PhD from Kyoto University in 2003. He was assigned as an assistant professor at the Department of Dermatology, Kyoto University (2003), a research associate at the Department of Microbiology and Immunology, UCSF (2003–2005), an associate professor at the Department of Dermatology at UOEH (2005–2008), and an associate professor at the Department of Dermatology, Kyoto University. His interests are cutaneous immunology, live imaging of the skin, and lipid biology. His hobbies are mountaineering, marathon, and blogging.

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Invited review articleNew concept of the pathogenesis of atopic dermatitis: Interplay among the barrier, allergy, and pruritus as a trinity

Abstract

Introduction

Section snippets

Stratum corneum and tight junction

Allergy/immunology

Pruritus

Future direction

Funding

J Allergy Clin Immunol

J Invest Dermatol

J Dermatol Sci

J Dermatol Sci

Dermatol Sin

Am J Pathol

Gastroenterology

Immunity

J Dermatol Sci

Methods Cell Biol

J Invest Dermatol

J Allergy Clin Immunol

J Dermatol Sci

J Allergy Clin Immunol

J Dermatol Sci

J Invest Dermatol

J Invest Dermatol

J Dermatol Sci

J Allergy Clin Immunol

J Invest Dermatol

J Dermatol Sci

J Dermatol Sci

J Am Acad Dermatol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Int Immunopharmacol

Immunity

J Invest Dermatol

J Dermatol Sci

J Allergy Clin Immunol

Cell

J Dermatol Sci

J Dermatol Sci

J Dermatol Sci

J Dermatol Sci

J Dermatol Sci

J Allergy Clin Immunol

Atopic dermatitis

N Engl J Med

Filaggrin mutations and atopy: consequences for future therapeutics

Expet Rev Clin Immunol

Early immune events in the induction of allergic contact dermatitis

Nat Rev Immunol

Stratum corneum pH in atopic dermatitis: impact on skin barrier function and colonization with Staphylococcus aureus

Am J Clin Dermatol

Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome

J Exp Med

Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis

Nat Genet

Claudin-based tight junctions are crucial for the mammalian epidermal barrier: a lesson from claudin-1-deficient mice

J Cell Biol

The cornified envelope: a model of cell death in the skin

Nat Rev Mol Cell Biol

Filaggrin in atopic dermatitis: flaky tail mice as a novel model for developing drug targets in atopic dermatitis

Inflamm Allergy Drug Targets

A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming

Nat Genet

Filaggrin-deficient mice exhibit TH17-dominated skin inflammation and permissiveness to epicutaneous sensitization with protein antigen

J Allergy Clin Immunol

Invited review article
New concept of the pathogenesis of atopic dermatitis: Interplay among the barrier, allergy, and pruritus as a trinity