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Progress in Understanding Atopic Dermatitis

       Introduction

      Atopic dermatitis (AD) is the most common chronic inflammatory skin disease, and its realm of basic mechanisms and predisposing factors is similarly wide. The Journal of Investigative Dermatology (JID) has recently published a surprisingly numerous collection of articles, comments, and reviews that scan the universe of basic information about AD. This review is directed toward using the JID Collections to provide a background and melding of research focuses in the current setting. This online commentary will attempt to consolidate and interweave some of the featured studies that have emerged. In the past century, most efforts to explain AD reflected allergic and immune mechanisms. With the 2006 revelation of a clear association between FLG deficiency and AD (
      • Palmer N.A.
      • Irvine A.D.
      • Terron-Kwiatkowski A.
      • Zhao Y.
      • Liao H.
      • Lee S.P.
      • et al.
      Common loss-of-function variants of the epidermal barier protein filaggrin are a major predisposing factor for atopic dermatitis.
      ), that focus began to shift to inclusion of epidermal barrier defects and their interaction with immune and inflammatory factors. This broadened approach has provided further fresh insights to genetic aspects, microbiome factors, and neural associations of skin pruritus and pain.

       Epidermal barrier

      Cellular and molecular abnormalities associated with AD have been detected during the past two decades, providing more detailed understanding beyond the clinical domains of allergy or neurodermatitis (
      • Eyerich S.
      • Eyerich K.
      • Traidl-Hoffmann C.
      • Biedermann T.
      Cutaneous barriers and skin immunity: differentiating a connected network.
      ). A major advance came with the genetic demonstration that significant numbers of AD patients had FLG deficiency that compromises the epidermal barrier, allowing penetration of bacteria, allergens, and environmental chemicals and pollutants. Increases of these xenobiotics in urban regions combined with barrier access has been shown to act on keratinocytes to trigger the transcription factor PXR (
      • Elentner A.
      • Schmuth M.
      • Yannoutsos N.
      • Eichmann T.O.
      • Gruber R.
      • Radner F.P.W.
      • et al.
      Epidermal overexpression of xenobiotic receptor PXR impairs the epidermal barrier and triggers Th2 immune response.
      ) and the aryl hydrocarbon receptor, both of which can work to cause AD worsening and even downstream release of TSLP and activation of the T helper (Th) type 2 pathway (
      • Hidaka T.
      • Ogawa E.
      • Kobayashi E.H.
      • Suzuki T.
      • Funayama R.
      • Nagashima T.
      • et al.
      The aryl hydrocarbon receptor AhR links atopic dermatitis and air pollution via induction of the neurotrophic factor artemin.
      ).
      Inflammation mediated by Th2 reactivity is seen as a prime pathway to AD. Subsequent studies have shown that epidermal barrier defects are generated by many factors, including bacteria (
      • Nakatsuji T.
      • Chen T.H.
      • Two A.M.
      • Chun K.A.
      • Narala S.
      • Geha R.S.
      • et al.
      Staphylococcus aureus exploits epidermal barrier defects in atopic dermatitis to trigger cytokine expression.
      ), increased skin pH (
      • Jang H.
      • Matsuda A.
      • Jung K.
      • Karasawa K.
      • Matsuda K.
      • Oida K.
      • et al.
      Skin pH is the master switch of kallikrein 5-mediated skin barrier destruction in a murine atopic dermatitis model.
      ), keratinocyte cytokines, and Th2-generated inflammation (
      • Hönzke S.
      • Wallmeyer L.
      • Ostrowski A.
      • Radbruch M.
      • Mundhenk L.
      • Schafer-Korting M.
      • et al.
      Influence of Th2 cytokines on the cornified envelope, tight junction proteins, and β-defensins in filaggrin-deficient skin equivalents.
      ). Also, many other deficient/defective barrier components may well predispose to skin inflammation. These include claudin-1 (
      • Furuse M.
      • Hata M.
      • Yoshida Y.
      • Haratake A.
      • Sugitani Y.
      • Noda T.
      • et al.
      Claudin-based tight junctions are crucial for the mammalian epidermal barrier: a lesson from claudin-1 deficient mice.
      ), corneodesmosin (
      • Oji V.
      • Eckl K.-M.
      • Aufenvenne K.
      • Natebus M.
      • Tarinski T.
      • Ackermann K.
      • et al.
      Loss of corneodesmosin leads to severe skin barrier defect, pruritus, and atopy: unraveling the peeling skin disease.
      ), LEKTI (
      • Igawa S.
      • Kishibe M.
      • Minami-Hori M.
      • Honma M.
      • Tsujimura H.
      • Ishikawa J.
      • et al.
      Incomplete KLK7 secretion and upregulated LEKTI expression underlie hyperkeratotic stratum corneum in atopic dermatitis.
      ), small proline-rich proteins (
      • Kelsell D.P.
      • Byrne C.
      SNPing at the epidermal barrier.
      ), and lipid components (
      • Kim D.
      • Lee N.R.
      • Park S.Y.
      • Jun M.
      • Lee K.
      • Kim S.
      • et al.
      As in atopic dermatitis, nonlesional skin in allergic contact dermatitis displays abnormalities in barrier function and ceramide content.
      ). Studies in mice have suggested that mast cells may even have a beneficial role in regulating epidermal barrier function and reducing inflammation (
      • Sehra S.
      • Serezani A.P.M.
      • Ocana J.A.
      • Travers J.B.
      • Kaplan M.H.
      Mast cells regulate epidermal barrier function and the development of allergic skin inflammation.
      ). Likewise, other studies have provided evidence of a two-way street for filaggrin-associated effects in AD, showing that inflammatory factors can act to reduce barrier function (
      • Elentner A.
      • Schmuth M.
      • Yannoutsos N.
      • Eichmann T.O.
      • Gruber R.
      • Radner F.P.W.
      • et al.
      Epidermal overexpression of xenobiotic receptor PXR impairs the epidermal barrier and triggers Th2 immune response.
      ,
      • Traidl S.
      • Kienlin P.
      • Begemann G.
      • Jing L.
      • Koelle D.M.
      • Werfel T.
      • et al.
      Patients with atopic dermatitis and history of eczema herpeticum elicit herpes simplex virus-specific type 2 immune responses.
      ).

       Cellular and molecular inflammatory mechanisms

      Through many decades, prominent AD comorbidities such as asthma, food allergy, and rhino-conjunctivitis have steered research toward immunological mechanisms, with the preponderant focus on IgE-related factors. It has been difficult, however, to find associations with the oft-noted but inconsistent presence of allergen-specific IgE, eosinophils, or mast cells in tissue and blood. During the past two decades, investigations of Th2 cells that secrete IL-4 and IL-13 have predominated. The practical benefits of these studies have been recently realized through the development of new agents that provide confirmation of the Th2 pathway.
      Another outgrowth of epidermal barrier studies was the realization that keratinocyte cytokines such as TSLP could act on dendritic cells and Th2 cells to augment immune and inflammatory responses in the skin and other organs, potentially influencing AD and asthma. A similar effect on Th2 cells contributes to increased pruritus via IL-31 effects (
      • Meng J.
      • Moriyama M.
      • Feld M.
      • Buddenkotte J.
      • Buhl T.
      • Szollosi A.
      • et al.
      New mechanism underlying IL-31-induced atopic dermatitis.
      ). Conversely, TSLP has been shown to act on keratinocytes to impair expression of antimicrobial proteins via a JAK/STAT mechanism, potentially contributing to infections in AD skin (
      • Lee H.
      • Ryu W.I.
      • Kim H.J.
      • Bae H.C.
      • Ryu H.J.
      • Shin J.J.
      • et al.
      TSLP down-regulates S100A7 and β-defensin 2 via the JAK2/STAT3-dependent mechanism.
      ).
      TSLP regulates a distinct group of immune cells in the skin called innate lymphoid cells (ILCs) that are enriched in the skin of AD patients and promote skin inflammation (
      • Kim B.S.
      • Siracusa M.C.
      • Saenz S.A.
      • Noti M.
      • Monticelli L.A.
      • Sonnenberg G.F.
      • et al.
      TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation.
      ). ILCs reside in the upper dermis near the epidermis, in proximity to T lymphocytes, and distinct population subtypes have been described in AD (
      • Bruggen M.C.
      • Bauer W.M.
      • Reininger B.
      • Clim E.
      • Captarencu C.
      • Steiner G.E.
      • et al.
      In situ mapping of innate lymphoid cells in human skin: evidence for remarkable differences between normal and inflamed skin.
      ). Trim 32, an innate antiviral protein associated with ILCs, has been found at low levels in AD skin, suggesting another possible pathway to explain AD patients’ susceptibility to herpes and other viral infections (
      • Gao L.
      • Bin L.
      • Rafaels N.M.
      • Huang L.
      • Potee J.
      • Ruczinski I.
      • et al.
      Targeted deep sequencing identifies rare ‘loss-of-function’ variants in IFNGR1 for risk of atopic dermatitis complicated by eczema herpeticum.
      ,
      • Liu Y.
      • Wang Z.
      • De La Torre R.
      • Barling A.
      • Tsujikawa T.
      • Hornick N.
      • et al.
      Trim32 Deficiency enhances Th2 immunity and predisposes to features of atopic dermatitis.
      ).

       Neural aspects

      Pruritus is perhaps the most important clinical feature associated with AD. Although this is obvious today, pruritus was often not included in severity assessments two decades ago. The recognition and study of itch has revealed a variety of factors that initiate and perpetuate itch in AD. However, as with immune and inflammatory pathways, progress tends to be piecemeal, with evidence of sodium and receptor potential channels and cytokine receptors, among others, being slowly added (
      • Azimi E.
      • Lerner E.A.
      The 7th World Congress on Itch.
      ,
      • Lerner E.A.
      Pathophysiology of itch.
      ). Itch in AD is primarily histamine independent (
      • Snyder L.M.
      • Kuzirian M.S.
      • Ross S.E.
      An unexpected role for TRPV4 in serotonin-mediated itch.
      ), a fact that is often ignored by practitioners, who divert patients from proper skin care with endless prescriptions of antihistamines.
      Studies in recent years have begun to identify neural pathways that begin with keratinocyte cytokines. TSLP, involved with Th2 immune pathways, also communicates with cutaneous sensory neurons to promote itch through activation of ion channels such as TRPV1 and TRPA1 (
      • Wilson S.R.
      • The L.
      • Batia L.M.
      • Beattie K.
      • Katibah G.E.
      • McClain S.P.
      • et al.
      The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch.
      ). These studies have led to identification of other TRP channels and sodium channels in nerves carrying itch responses (
      • Akiyama T.
      • Ivanov M.
      • Nagamine M.
      • Davoodi A.
      • Carstens M.I.
      • Ikoma A.
      • et al.
      Involvement of TRPV4 in serotonin-evoked scratching.
      ). A prominent histamine-independent mediator of itch in AD is IL-31, which forms a neuroimmune link between the Th2 pathway and sensory nerves. A recent study showed that IL-31, binding to its receptor in dorsal root ganglion cells, not only caused itch but also increased brain-derived natriuretic peptide (i.e., BNP) synthesis and release, which in turn can mediate release of chemokines and cytokines from keratinocytes and dendritic cells (
      • Meng J.
      • Moriyama M.
      • Feld M.
      • Buddenkotte J.
      • Buhl T.
      • Szollosi A.
      • et al.
      New mechanism underlying IL-31-induced atopic dermatitis.
      ). In chronic itch, neuronal IL-4Rα and JAK signaling mediates itch sensation, a discovery that has led to effective therapeutic interventions (
      • Oetjen L.K.
      • Mack M.R.
      • Feng J.
      • Whelan T.M.
      • Niu H.
      • Guo C.J.
      • et al.
      Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch.
      ).
      Some of the emerging therapies for AD highlight benefits on cells in the Th2 and IL-31 pathways. Nemolizumab, a monoclonal antibody, can block the IL-31 receptor and reduce itch independently.22 The newly approved monoclonal antibody dupilumab blocks the IL-4α receptor, reducing both itch and inflammation (
      • Simpson E.L.
      • Bieber T.
      • Guttman-Yassky E.
      • Beck L.A.
      • Blauvelt A.
      • Cork M.J.
      • et al.
      Two phase 3 trials of dupilumab versus placebo in atopic dermatitis.
      ). Another pathway that may influence itch in AD has been unexpectedly suggested by recent clinical trials. Past studies of mononuclear leukocytes had shown reduced cyclic adenosine monophosphate control, due to overactive intracellular phosphodiesterase activity (
      • Chan S.C.
      • Reifsnyder D.
      • Beavo J.A.
      • Hanifin J.A.
      Immunohistochemical characterization of the distinct monocyte cyclic AMP-phosphodiesterase from patients with atopic dermatitis.
      ), and this led to development of topical phosphodiesterase inhibitors, which can have benefits in mild to moderate disease. A surprising observation has been the fairly rapid reductions in itch, possibly even preceding evidence of reduced skin inflammation (
      • Garcia A.M.
      • Martinez A.
      • Gil C.
      Enhancing cAMP levels as strategy for the treatment of neuropsychiatric disorders.
      ). Genetic studies are also indicating distinct patterns of expression in pruritic AD skin that contrast with psoriasis (
      • Nattkemper L.A.
      • Tey H.L.
      • Valdes-Rodriguez R.
      • Lee H.
      • Mollanazer N.K.
      • Albornoz C.
      • et al.
      The genetics of chronic itch: gene expression in the skin of patients with atopic dermatitis and psoriasis with severe itch.
      ).

       Infections and microbiome associations with AD

      The realm of infections and skin colonization is complex and multifaceted. Studies over many decades showed impaired delayed hypersensitivity and increased frequency of viral and bacterial infections (
      • Gao L.
      • Bin L.
      • Rafaels N.M.
      • Huang L.
      • Potee J.
      • Ruczinski I.
      • et al.
      Targeted deep sequencing identifies rare ‘loss-of-function’ variants in IFNGR1 for risk of atopic dermatitis complicated by eczema herpeticum.
      ,
      • Traidl S.
      • Kienlin P.
      • Begemann G.
      • Jing L.
      • Koelle D.M.
      • Werfel T.
      • et al.
      Patients with atopic dermatitis and history of eczema herpeticum elicit herpes simplex virus-specific type 2 immune responses.
      ). The association between AD and staphylococcal infections has also been known for decades and, although the incidence of colonization on children may be lower, it may occur earlier and tends to affect patients with more severe disease (
      • Simpson E.L.
      • Villarreal M.
      • Jepson B.
      • Rafaels N.
      • David G.
      • Hanifin J.
      • et al.
      Patients with atopic dermatitis colonized with Staphylococcus aureus have a distinct phenotype and endotype.
      ). Certainly, the association is strong and of genetic interest for both bacteria and host (
      • Harkins C.P.
      • Pettigrew K.A.
      • Oravcova K.
      • Gardner J.
      • Hearn R.M.R.
      • Rice D.
      • et al.
      The microevolution and epidemiology of Staphylococcus aureus colonization during atopic eczema disease flare.
      ). Current prevention studies of Staphylococcus aureus are increasing our understanding of the relationship with AD. A recent prospective study from Europe showed that S. aureus can precede development of infant AD, with increased colonization even 2 months earlier than appearance of AD, and that onset was earlier in S. aureus–positive infants (
      • Meylan P.
      • Lang C.
      • Mermoud S.
      • Johannsen A.
      • Norrneberg S.
      • Hohl D.
      • et al.
      Skin colonization by Staphylococcus aureus precedes the clinical diagnosis of atopic dermatitis in infancy.
      ). This contrasted with an earlier study indicating that S. aureus colonized after AD onset but suggesting that different staphylococcal variants might be causal (
      • Kennedy E.A.
      • Connolly J.
      • Hourihane J.O.
      • Fallon P.G.
      • McLean W.H.I.
      • Murray D.
      • et al.
      Skin microbiome before development of atopic dermatitis: early colonization with commensal staphylococci at 2 months is associated with a lower risk of atopic dermatitis at 1 year.
      ). Studies assessing the interaction between S. aureus and the epidermis have shown proinflammatory and barrier-damaging effects on keratinocytes (
      • Williams M.R.
      • Gallo R.L.
      Evidence that human skin microbiome dysbiosis promotes atopic dermatitis.
      ) and have suggested possible target avenues for new therapies.

       Overview

      AD continues to be a complex disease, very difficult to define and delineate. This review has considered some of the main areas of research focus at the present time. In the 12 years since the revelation of the connection between AD and FLG deficiency initiated the intense focus on the epidermal barrier, a wide range of studies has provided new reflections on inflammatory and immune pathways, neural interactions, and genetic features that relate to multiple aspects (
      • Blunder S.
      • Ruhl R.
      • Moosbrugger-Martinz V.
      • Krimmel C.
      • Geisler A.
      • Zhu H.
      • et al.
      Alterations in epidermal eicosanoid metabolism contribute to inflammation and impaired late differentiation in FLG-mutated atopic dermatitis.
      ,
      • Chen L.Y.
      • Yang-Yen H.F.
      • Tsai C.C.
      • Thio C.L.
      • Chuang H.L.
      • Yang L.T.
      • et al.
      Protein palmitoylation by ZDHHC13 protects skin against microbial-driven dermatitis.
      ,
      • Miyai M.
      • Hamada M.
      • Moriguchi T.
      • Hiruma J.
      • Kamitani-Kawamoto A.
      • Watanabe H.
      • et al.
      Transcription factor MafB coordinates epidermal keratinocyte differentiation.
      ). All of those segments have generated fresh ideas aimed at therapeutic possibilities (
      • Johnston A.
      Resolving inflammation by targeting an ancient innate immune sensor with a bacterial metabolite.
      ), and some new and highly beneficial products have begun to enter a realm of much-needed patient care with products for both milder childhood disease and for patients with severe AD.

      Conflict of Interest

      The author states no conflict of interest.

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      Linked Article

      • Influence of Th2 Cytokines on the Cornified Envelope, Tight Junction Proteins, and β-Defensins in Filaggrin-Deficient Skin Equivalents
        Journal of Investigative DermatologyVol. 136Issue 3
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          Atopic dermatitis is a chronic skin condition with complex etiology. It is characterized by skin barrier defects and T helper type 2 (Th2)-polarized inflammation. Although mutations in the filaggrin gene are known to be prominent genetic risk factors for the development of atopic dermatitis, the interdependency between these and an altered cytokine milieu is not fully understood. In this study, we evaluated the direct effects of filaggrin deficiency on the cornified envelope, tight junction proteins, and innate immune response, and report the effects of Th2 cytokines in normal and filaggrin-deficient skin equivalents.
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      • Mast Cells Regulate Epidermal Barrier Function and the Development of Allergic Skin Inflammation
        Journal of Investigative DermatologyVol. 136Issue 7
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          Atopic dermatitis is a chronic inflammatory skin disease characterized by infiltration of eosinophils, T helper cells, and mast cells. The role of mast cells in atopic dermatitis is not completely understood. To define the effects of mast cells on skin biology, we observed that mast cells regulate the homeostatic expression of epidermal differentiation complex and other skin genes. Decreased epidermal differentiation complex gene expression in mice that genetically lack mast cells (KitW–sh/W–sh mice) is associated with increased uptake of protein antigens painted on the skin by dendritic cells (DCs) compared with similarly treated wild-type mice, suggesting a protective role for mast cells in exposure to nominal environmental allergens.
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      • Increasing Comorbidities Suggest that Atopic Dermatitis Is a Systemic Disorder
        Journal of Investigative DermatologyVol. 137Issue 1
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          Atopic dermatitis comorbidities extend well beyond the march to allergic conditions (food allergy, asthma, allergic rhinitis, allergic conjunctivitis, and eosinophilic esophagitis), suggesting both cutaneous and systemic immune activation. In reviewing atopic dermatitis comorbidities, Councilors of the International Eczema Council found a strong pattern of immune activation in peripheral blood and the propensity to both skin and systemic infections. Associations with cardiovascular, neuropsychiatric, and malignant diseases were increasingly reported, but confirmation of their link with atopic dermatitis requires longitudinal studies.
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      • Staphylococcus aureus Exploits Epidermal Barrier Defects in Atopic Dermatitis to Trigger Cytokine Expression
        Journal of Investigative DermatologyVol. 136Issue 11
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          Patients with atopic dermatitis (AD) have an abnormal skin barrier and are frequently colonized by S. aureus. In this study we investigated if S. aureus penetrates the epidermal barrier of subjects with AD and sought to understand the mechanism and functional significance of this entry. S. aureus was observed to be more abundant in the dermis of lesional skin from AD patients. Bacterial entry past the epidermis was observed in cultured human skin equivalents and in mice but was found to be increased in the skin of cathelicidin knockout and ovalbumin-sensitized filaggrin mutant mice.
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