Langerhans and inflammatory dendritic epidermal cells in atopic dermatitis are tolerized toward <scp>TLR</scp>2 activation

Iwamoto, Kazumasa; Nümm, Tim Joachim; Koch, Susanne; Herrmann, Nadine; Leib, Nicole; Bieber, Thomas

doi:10.1111/all.13460

Cited by 47 publications

(43 citation statements)

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“…Among the pattern recognizing receptors, TLR2 expressed on cell surface is known to be responsible for the host defense against S. aureus . Moreover, polymorphisms in TLR2 are reported to be associated with the severity of AD and function of TLR2 is downregulated in AD skin . Furthermore, lipoproteins of S. aureus are known to induce IL‐6 production in keratinocytes via the TLR1/TLR2 pathway .…”

Section: Discussionmentioning

confidence: 99%

Staphylococcus aureus from atopic dermatitis skin accumulates in the lysosomes of keratinocytes with induction of IL‐1α secretion via TLR9

Moriwaki

Iwamoto

Niitsu

et al. 2018

Allergy

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Background: Staphylococcus aureus (S. aureus) is frequently detected in the skin of patients with atopic dermatitis (AD), and involved in the flare of AD. There are some evidence-specific strains of S. aureus affect the severity of AD. However, the mechanism of predominant colonization and the aggravation of dermatitis by certain strains of S. aureus in the patients with AD are still unknown.Objective: To reveal the characteristics of S. aureus from patients with AD (S. aureus-AD), we analyzed the interaction of S. aureus-AD and keratinocytes in comparison with those of S. aureus laboratory strains (S. aureus-stand.). Methods:We stimulated HaCaT cells, keratinocyte cell line, and human epidermal keratinocytes by heat-killed S. aureus strains, then evaluated immune response of keratinocytes by ELISA, immunofluorescence staining, and flow cytometry.Results: Upon incubation with keratinocytes, three out of four strains of heat-killed S. aureus-AD were strongly agglutinated inside the cytoplasm. In the cells, they are located in lysosomes and promoted the secretion of interleukin-1α (IL-1α). These reactions were not observed by any of four strains of S. aureus-stand. and S. epidermidis and were abolished by the treatment of S. aureus with proteinase K. Moreover, the IL-1α secretion was diminished by the inhibition of Toll-like receptor 9 (TLR9). Conclusion: S. aureus-AD accumulates in lysosome of keratinocytes by means of bacterial cell wall proteins and induces IL-1α via TLR9. K E Y W O R D S atopic dermatitis, dermatology, innate immunity, microbiome, staphylococcus aureus 1 | INTRODUCTION Atopic dermatitis (AD) is a common chronic skin disease characterized by pruritus and recurrent eczematous lesions. 1 There is a strong correlation between filaggrin (FLG) mutations and AD, but not all carriers of FLG mutation develop AD, 2 suggesting the involvement of other causative or aggravating factors in the pathogenesis of AD. Many patients with AD frequently suffer from cutaneous infections by Staphylococcus aureus (S. aureus). Moreover, S. aureus is commonly isolated from patients with AD, even from apparently non-lesion skin. 3 Furthermore, S. aureus colonization has been shown to be associated with AD severity and observed even before the onset of AD in infants. 4 A previous study of the skin microbiome of patients with AD revealed reduced diversity and high Staphylococcus proportions in flares of untreated AD, 5 whereas Staphylococcus epidermidis (S. epidermidis) predominates on the skin surface of healthy individuals. In murine models, S. aureus colonization and low diversity of the microbiome drive AD-like lesions in the skin. 6Compared to standard S. aureus strains, S. aureus isolated from AD skin are able to induce different innate immune responses. S. aureus from AD skin are internalized into keratinocytes and accumulate in lysosomes with inducing IL-1α secretion via TLR9. Specific surface proteins of S. aureus from AD skin are responsible for their internalization.

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Section: Discussionmentioning

confidence: 99%

Staphylococcus aureus from atopic dermatitis skin accumulates in the lysosomes of keratinocytes with induction of IL‐1α secretion via TLR9

Moriwaki

Iwamoto

Niitsu

et al. 2018

Allergy

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“… 2 Toll-like receptor-2 (TLR-2)-sensing of S aureus by Langerhans cells and inflammatory dendritic epidermal cells has also been found to be impaired in patients with AD. 16 Natural killer cells have recently been found to be deficient in patients with AD. 17 This deficiency may also contribute to increased type 2 inflammation owing to a potential counter-regulatory mechanism between the natural killer cells and type 2 inflammation.…”

Section: What Causes An Increase In Infections In Ad?mentioning

confidence: 99%

The infectious complications of atopic dermatitis

Wang

Boguniewicz

et al. 2021

Annals of Allergy, Asthma & Immunology

113

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Objective Atopic dermatitis (AD) is a chronic inflammatory skin disease that is complicated by an increased risk for skin and systemic infections. Preventive therapy for AD is based on skin barrier improvement and anti-inflammatory treatments, whereas overt skin and systemic infections require antibiotics or antiviral treatments. This review updates the pathophysiology, diagnosis, management, controversy of antibiotic use, and potential treatments of infectious complications of AD. Data Sources Published literature obtained through PubMed database searches and clinical pictures. Study Selections Studies relevant to the mechanisms, diagnosis, management, and potential therapy of infectious complications of AD. Results Skin barrier defects, type 2 inflammation, Staphylococcus aureus colonization, and cutaneous dysbiosis are the major predisposing factors for the increased infections in AD. Although overt infections require antibiotics, the use of antibiotics in AD exacerbation remains controversial. Conclusion Infectious complications are a comorbidity of AD. Although not common, systemic bacterial infections and eczema herpeticum can be life-threatening. Preventive therapy of infections in AD emphasizes skin barrier improvement and anti-inflammatory therapy. The use of antibiotics in AD exacerbation requires further studies.

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“…While their function still remains unknown, functional differences have been reported between IDECs and LCs, with the former showing no signs of dendritic extensions through tight junctions to process antigens unlike what has been shown by LCs (126). Furthermore, both IDECs and LCs within atopic dermatitis skin have been shown to have markedly lower TLR2 expression compared to LCs in healthy skin, while IDECs and not LCs have markedly higher levels of the maturation marker CD83 and MHC class I and class II molecules (127).…”

Section: Dendritic Cell Subsets and Ontogenymentioning

confidence: 99%

Human Dendritic Cell Subsets, Ontogeny, and Impact on HIV Infection

et al. 2019

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Dendritic cells (DCs) play important roles in orchestrating host immunity against invading pathogens, representing one of the first responders to infection by mucosal invaders. From their discovery by Ralph Steinman in the 1970s followed shortly after with descriptions of their in vivo diversity and distribution by Derek Hart, we are still continuing to progressively elucidate the spectrum of DCs present in various anatomical compartments. With the power of high-dimensional approaches such as single-cell sequencing and multiparameter cytometry, recent studies have shed new light on the identities and functions of DC subtypes. Notable examples include the reclassification of plasmacytoid DCs as purely interferon-producing cells and re-evaluation of intestinal conventional DCs and macrophages as derived from monocyte precursors. Collectively, these observations have changed how we view these cells not only in steady-state immunity but also during disease and infection. In this review, we will discuss the current landscape of DCs and their ontogeny, and how this influences our understanding of their roles during HIV infection.

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Langerhans and inflammatory dendritic epidermal cells in atopic dermatitis are tolerized toward TLR2 activation

Abstract: Our results suggest that TLR2-mediated sensing of S. aureus-derived signals is strongly impaired in LC from AD skin. This phenomenon may partly contribute to the immune deviation in AD and the lack of S. aureus clearance.

Cited by 47 publications

References 62 publications

Staphylococcus aureus from atopic dermatitis skin accumulates in the lysosomes of keratinocytes with induction of IL‐1α secretion via TLR9

Staphylococcus aureus from atopic dermatitis skin accumulates in the lysosomes of keratinocytes with induction of IL‐1α secretion via TLR9

The infectious complications of atopic dermatitis

Human Dendritic Cell Subsets, Ontogeny, and Impact on HIV Infection

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