Selective impairment of Toll-like receptor 2–mediated proinflammatory cytokine production by monocytes from patients with atopic dermatitis

Hasannejad, Habib; Takahashi, Ryōsuke; Kimishima, Momoko; Hayakawa, Kazuhito; Shiohara, Tetsuo

doi:10.1016/j.jaci.2007.04.010

Cited by 81 publications

(85 citation statements)

References 34 publications

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“…The missing upregulation of TLR2 may contribute to the susceptibility for gram-positive skin infection in atopic skin. This is in line with the previously described impaired innate immune response in atopic skin comprising impaired function of TLR2 signalling pathway compared to psoriasis (20,23,24).…”

Section: Resultssupporting

confidence: 92%

TLR2 and TLR4 expression in atopic dermatitis, contact dermatitis and psoriasis

Panzer

Blobel

Fölster‐Holst

et al. 2014

Experimental Dermatology

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The aim of the study was to investigate the expression of Toll-like receptors (TLRs) 2 and 4 on keratinocytes in atopic dermatitis, contact dermatitis, and psoriasis by PCR and by immunohistochemistry including confocal microscopy. Confocal microscopy revealed a granular intra-cellular expression pattern for TLR 2 and a homogenous intra-cellular expression pattern for TLR 4 in normal and diseased skin. TLR 2 was constitutively expressed in the suprabasal layers in normal skin, but limited to the basal epidermis in diseased skin. TLR 4 expression was concentrated to the basal layers in normal skin, whereas it was pronounced in upper layers in diseased skin. The shift in the TLR expression may be related to the disturbed skin barrier and a need for enhanced immune surveillance because of invading microbes. Also, there must be a balance between sufficient immune response and overstimulation.Abbreviation: TLR, Toll-like receptor.

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Section: Resultssupporting

confidence: 92%

TLR2 and TLR4 expression in atopic dermatitis, contact dermatitis and psoriasis

Panzer

Blobel

Fölster‐Holst

et al. 2014

Experimental Dermatology

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“…It has been suggested that upregulated TLR expression in psoriatic skin contributes to disease pathophysiology by increasing the local production of antimicrobial peptides, and stimulating cutaneous immune responses and epidermal hyperproliferation (3,33). In contrast, monocytes from AD patients displayed significantly impaired TLR2-mediated production of the proinflammatory cytokines IL-1b and TNF-a (47). Additionally, the immunologic factors involved in the pathogenesis of AD are associated with upregulated IgE reactivity, and increased numbers of mast cells, eosinophils, and CD4-activated Th2 cells (34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

Autophagy Negatively Regulates Keratinocyte Inflammatory Responses via Scaffolding Protein p62/SQSTM1

Lee

Shin

Yuk

et al. 2011

The Journal of Immunology

189

166

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The scaffolding adaptor protein p62/SQSTM1 (p62) has been shown to be an autophagy receptor that acts as a link between the ubiquitination and autophagy machineries. However, the roles of autophagy and p62 in human keratinocytes are not well understood. In this study, we show that keratinocyte autophagy negatively regulates p62 expression, which is essential for the prevention of excessive inflammation and the induction of cathelicidin in human keratinocytes. Stimulation of TLR2/6 or TLR4 in primary human keratinocytes robustly activated autophagy pathways and up-regulated p62 expression through induction of NADPH oxidases 2 and 4 and the generation of reactive oxygen species. MyD88 and TNFR-associated factor 6, key signaling molecules that mediate TLR activation, played an essential role in the induction of autophagy and p62 expression. Additionally, blockade of autophagy significantly increased the generation of inflammatory cytokines and expression of p62 in primary human keratinocytes. Notably, silencing hp62 through RNA interference resulted in a significant decrease in NF-κB activation, inflammatory cytokine production, cathelicidin expression, and cell proliferation (as well as cyclin D1 expression) in keratinocytes. Epidermal expression of p62 was further found to be significantly higher in psoriatic skin than in skin affected by atopic dermatitis or from healthy controls. Collectively, our data provide new insights into the roles of autophagy and p62 in controlling cutaneous inflammation.

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“…TLR2 provides an important link between innate and adaptive immunity, particularly by modulating the Th2 response in atopic individuals (34,35). However, there are conflicting results regarding which mechanisms are involved in the modulation of the Th1/Th2 balance in experimental allergic airway disease, depending on the timing of antigenic stimulation, the dosage of different TLR2 agonists, and the genetic background of animal models.…”

Section: Discussionmentioning

confidence: 99%

TLR2 Agonists Enhance CD8+Foxp3+ Regulatory T Cells and Suppress Th2 Immune Responses during Allergen Immunotherapy

Tsai

Yang

Niu

et al. 2010

The Journal of Immunology

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Pam3CSK4, a synthetic TLR2 ligand, has been shown to expand CD4+ regulatory T cells (Treg cells). Less is known about the function of CD8+ Treg cells than about the function of CD4+ Treg cells generated during allergen-specific immunotherapy (IT). This study investigated whether Dermatophagoides pteronyssinus-specific IT could expand the CD8+CD25+Foxp3+ Treg population and whether Pam3CSK4 could enhance the Treg population. PBMCs were isolated from healthy control subjects and from mite-sensitive asthmatic patients during IT at three specific times: before IT and 6 mo and 1 y after the maximum-tolerated dose. This study was performed without a placebo-controlled group. D. pteronyssinus-specific IT induced a significant increase in CD8+Foxp3+ Treg cells expressing intracellular IL-10 and granzyme B. Costimulation of PBMCs with Pam3CSK4 and D. pteronyssinus 2 expanded the CD8+CD25+Foxp3+ Treg population and inhibited D. pteronyssinus 2-induced IL-4 production. Pam3CSK4-treated CD8+CD25+ Treg cells directly suppressed CD4+ T cell proliferation by cell-contact inhibition. TUNEL revealed that CD8+CD25+ Treg cells, but not CD4+CD25+ Treg cells, directly induced CD4+CD45ROhi+ apoptosis. Our results provide direct evidence that Pam3CSK4 induces an immunomodulatory effect by inducing CD8+ Treg cells; therefore, it may be a good adjuvant for the treatment of mite allergies.

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Selective impairment of Toll-like receptor 2–mediated proinflammatory cytokine production by monocytes from patients with atopic dermatitis

Cited by 81 publications

References 34 publications

TLR2 and TLR4 expression in atopic dermatitis, contact dermatitis and psoriasis

TLR2 and TLR4 expression in atopic dermatitis, contact dermatitis and psoriasis

Autophagy Negatively Regulates Keratinocyte Inflammatory Responses via Scaffolding Protein p62/SQSTM1

TLR2 Agonists Enhance CD8+Foxp3+ Regulatory T Cells and Suppress Th2 Immune Responses during Allergen Immunotherapy

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