Toll-like receptor 2 ligands promote chronic atopic dermatitis through IL-4–mediated suppression of IL-10

Kaesler, Susanne; Volz, Thomas; Skabytska, Yuliya; Köberle, Martin; Hein, Ulrike; Chen, Ko-Ming; Guenova, Emmanuella; Wölbing, Florian; Röcken, Martin; Biedermann, Tilo

doi:10.1016/j.jaci.2014.02.017

Cited by 99 publications

(84 citation statements)

References 50 publications

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“…13 However, our investigations favor the view that innate immune cells actively take part in S. aureus-accentuated AD symptoms by focusing on the NOD2/ TLR2-mediated activation of basophils, eosinophils, and dermal fibroblasts. NOD2 and TLR2 are the pivotal PRRs responsible for the immune recognition of S. aureus and are prevalently expressed on innate immune cells, including basophils and eosinophils.…”

Section: Discussionmentioning

confidence: 78%

“…10,11 TLR2-deficient mice are highly susceptible to S. aureus invasion, and macrophages from these mice release less interleukin (IL)-6 and IL-10 in response to heat-killed S. aureus. 12 Importantly, TLR2 is involved in AD-associated immune dysregulation 13 because the TLR2 ligand PGN (but not the TLR4 ligand lipopolysaccharide) activates basophils to secrete IL-4 and IL-13 in both an IgE-dependent and IgE-independent manner. 14 Basophils and eosinophils have been reported to be associated with a variety of skin diseases, including AD.…”

Section: Introductionmentioning

confidence: 99%

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NOD2 and TLR2 ligands trigger the activation of basophils and eosinophils by interacting with dermal fibroblasts in atopic dermatitis-like skin inflammation

et al. 2015

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The skin of patients with atopic dermatitis (AD) has a unique predisposition for colonization by Staphylococcus aureus (S. aureus), which contributes to the inflammation and grim prognosis of AD. Although the mechanism underlying the S. aureus-induced exacerbation of AD remains unclear, recent studies have found a pivotal role for pattern recognition receptors in regulating the inflammatory responses in S. aureus infection. In the present study, we used a typical mouse model of AD-like skin inflammation and found that S. aureus-associated nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and toll-like receptor 2 (TLR2) ligands exacerbated AD-like symptoms, which were further deteriorated by the in vivo expansion of basophils and eosinophils. Subsequent histological analyses revealed that dermal fibroblasts were pervasive in the AD-like skin lesions. Co-culture of human dermal fibroblasts with basophils and eosinophils resulted in a vigorous cytokine/chemokine response to the NOD2/TLR2 ligands and the enhanced expression of intercellular adhesion molecule-1 on the dermal fibroblasts. Basophils and eosinophils were primarily responsible for the AD-related cytokine/chemokine expression in the co-cultures. Direct intercellular contact was necessary for the crosstalk between basophils and dermal fibroblasts, while soluble mediators were sufficient to mediate the eosinophil-fibroblast interactions. Moreover, the intracellular p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, and nuclear factor-kappa B signaling pathways were essential for NOD2/TLR2 ligand-mediated activation of basophils, eosinophils, and dermal fibroblasts in AD-related inflammation. This study provides the evidence of NOD2/TLR2-mediated exacerbation of AD through activation of innate immune cells and therefore sheds light on a novel mechanistic pathway by which S. aureus contributes to the pathophysiology of AD. Cellular & Molecular Immunology

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Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

NOD2 and TLR2 ligands trigger the activation of basophils and eosinophils by interacting with dermal fibroblasts in atopic dermatitis-like skin inflammation

et al. 2015

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“…Another study conducted on mice [6] demonstrated that the TLR2 ligand-induced release of IL-10 from bone marrow-derived dendritic cells was inhibited by IL-4. Together, these reports suggest that Th2 cell-skewed conditions in expectant mothers and/or neonates may result in immune programming that suppresses the transcription of IL-10.…”

Section: Discussionmentioning

confidence: 99%

“…IL-10 producing dendritic cells primed by bacteria helps induce regulatory T cells through the TLR2 signal, leading to the suppression of T helper (Th)2-mediated inflammation [4]. Reduced microbial exposure or dysfunction of this pathway may impede IL-10-mediated immune suppression in allergic responses [5, 6]. Oral administration of gram-positive bacteria reportedly alleviates AD symptoms and increases serum IL-10 concentration in children [7].…”

Section: Introductionmentioning

confidence: 99%

Low Interleukin 10 Production at Birth Is a Risk Factor for Atopic Dermatitis in Neonates with <b><i>Bifidobacterium</i></b> Colonization

Suzuki

Campos-Alberto

Morita

et al. 2018

Int Arch Allergy Immunol

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Background: Altered regulatory immune responses to microbial stimuli and intestinal colonization of beneficial bacteria early in life may contribute to the development of allergic diseases (e.g., atopic dermatitis [AD]). However, few reports have investigated these factors simultaneously. The purpose of this study was to analyze neonatal immune responses to microbial stimuli as well as intestinal colonization of beneficial bacteria, in relation to the development of AD in a birth cohort. Methods: Pregnant women were recruited, and their infants were followed up until 7 months of age. Levels of interleukin (IL)-10 released from cord-blood mononuclear cells (CBMCs) stimulated with heat-killed gram-positive bacteria (Bifidobacterium bifidum and Lactobacillus rhamnosus GG) and Lactobacillus-derived peptidoglycan were measured. Fecal Bifidobacterium counts at 4 days and 1 month were quantified using real-time polymerase chain reaction. The development of AD was determined by means of a questionnaire at 7 months of age. Results: The levels of released IL-10 were significantly lower in infants with AD (n = 17) than in infants without AD (n = 53) for all stimuli. In infants with fecal Bifidobacterium, the incidence of AD was inversely associated with the release of IL-10 from cord blood mononuclear cells. Conclusion: Our findings suggest that impaired IL-10 production in response to microbial stimuli at birth may be associated with an increased risk of developing infantile AD, even in infants with early colonization of intestinal bifidobacteria.

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“…In einem Mausmodell der atopischen Dermatitis konnte gezeigt werden, dass eine durch Th2-Zellen und IL-4 mediierte Entzündung der Haut zunächst einen selbstlimitierenden Verlauf nimmt. Kommt es aber in einem von IL-4 dominierten Zytokinmilieu zur Aktivierung des angeborenen Immunsystems durch TLR2-Liganden, so ist die Entzündungsreaktion nicht nur stär-ker, sondern persistiert auch deutlich län-ger -sie chronifiziert [15]. Die dabei zugrunde liegenden Mechanismen konnten schrittweise aufgedeckt werden.…”

Section: » Die Funktion Der Antimikrobiellen Peptide Besteht In Der Aunclassified

The role of the innate immune system in atopic dermatitis

et al. 2015

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The mechanisms how the innate immune system detects microbes and mounts a rapid immune response have been more and more elucidated in the past years. Subsequently it has been shown that innate immunity also shapes adaptive immune responses and determines their quality that can be either inflammatory or tolerogenic. As atopic dermatitis is characterized by disturbances of innate and adaptive immune responses, colonization with pathogens and defects in skin barrier function, insight into mechanisms of innate immunity has helped to understand the vicious circle of ongoing skin inflammation seen in atopic dermatitis patients. Elucidating general mechanisms of the innate immune system and its functions in atopic dermatitis paves the way for developing new therapies. Especially the novel insights into the human microbiome and potential functional consequences make the innate immune system a very fundamental and promising target. As a result atopic dermatitis manifestations can be attenuated or even resolved. These currently developed strategies will be introduced in the current review.

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Toll-like receptor 2 ligands promote chronic atopic dermatitis through IL-4–mediated suppression of IL-10

Cited by 99 publications

References 50 publications

NOD2 and TLR2 ligands trigger the activation of basophils and eosinophils by interacting with dermal fibroblasts in atopic dermatitis-like skin inflammation

NOD2 and TLR2 ligands trigger the activation of basophils and eosinophils by interacting with dermal fibroblasts in atopic dermatitis-like skin inflammation

Low Interleukin 10 Production at Birth Is a Risk Factor for Atopic Dermatitis in Neonates with <b><i>Bifidobacterium</i></b> Colonization

The role of the innate immune system in atopic dermatitis

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