Infected atopic dermatitis lesions contain pharmacologic amounts of lipoteichoic acid

Travers, Jeffrey B.; Kozman, Amal; Mousdicas, Nico; Saha, Chandan; Landis, Megan N.; Al-Hassani, Mohammed; Yao, Weiguo; Yao, Yongxue; Hyatt, Ann Marie; Sheehan, Michael P.; Haggstrom, Anita N.; Kaplan, Mark H.

doi:10.1016/j.jaci.2009.09.052

Cited by 69 publications

(88 citation statements)

References 34 publications

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“…Subsequently, S. aureus promotes AD by stimulating a strong proinflammatory response (7). S. aureus proteins, such as hemolysin ␣ (HLA), staphylococcal protein A (SPA), and lipoteichoic acids (LTA), promote proinflammatory cytokine production from keratinocytes (7)(8)(9)(10)(11). However, this stimulation requires the concurrent presence of a surfactant, such as SDS (11).…”

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Staphlyococcus aureus Phenol-Soluble Modulins Stimulate the Release of Proinflammatory Cytokines from Keratinocytes and Are Required for Induction of Skin Inflammation

et al. 2015

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Staphylococcus aureus is a human commensal that colonizes the skin. While it is normally innocuous, it has strong associations with atopic dermatitis pathogenesis and has become the leading cause of skin and soft tissue infections in the United States. The factors that dictate the role of S. aureus in disease are still being determined. In this work, we utilized primary keratinocyte culture and an epidermal murine colonization model to investigate the role of S. aureus phenol-soluble modulins (PSMs) in proinflammatory cytokine release and inflammation induction. We demonstrated that many species of Staphylococcus are capable of causing release of interleukin 18 (IL-18) from keratinocytes and that S. aureus PSMs are necessary and sufficient to stimulate IL-18 release from keratinocytes independently of caspase 1. Further, after 7 days of epicutaneous exposure to wild-type S. aureus, but not S. aureus ⌬psm, we saw dramatic changes in gross pathology, as well as systemic release of proinflammatory cytokines. This work demonstrates the importance of PSM peptides in S. aureus-mediated inflammatory cytokine release from keratinocytes in vitro and in vivo and further implicates PSMs as important contributors to pathogenesis. Staphylococcus aureus is a human commensal that lives in the nose, skin, and throat in approximately 30% of the human population (1, 2). While S. aureus is usually harmless, it is an opportunistic pathogen that has become a leading cause of nosocomial infections in the United States (3) and can manifest as skin and soft tissue infections, infective endocarditis, osteomyelitis, and sepsis (1). Further, it has a role in exacerbation of atopic dermatitis (AD), a chronic inflammatory disease of the skin that affects up to 20% of children and up to 3% of adults (4, 5). Chronic cutaneous inflammation during AD results in increased production of extracellular matrix components that permit attachment of S. aureus (6). Subsequently, S. aureus promotes AD by stimulating a strong proinflammatory response (7). S. aureus proteins, such as hemolysin ␣ (HLA), staphylococcal protein A (SPA), and lipoteichoic acids (LTA), promote proinflammatory cytokine production from keratinocytes (7-11). However, this stimulation requires the concurrent presence of a surfactant, such as SDS (11).Keratinocytes serve as the first line of defense against cutaneous pathogens and are able to stimulate an immune response by releasing cytokines, defensins, and antimicrobial cationic peptides, such as LL-37, to fight off pathogens (12). One cytokine that is produced by keratinocytes and has a role in promoting AD is interleukin 18 (IL-18) (13,14). IL-18 is a proinflammatory cytokine that is cleaved and activated primarily by caspase 1 (15). Caspase 1 activation occurs following exposure to danger-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs), which stimulate the activation of the inflammasome (16). Caspase 1 activation can also result in the activation of the proinflammatory cytokine IL-1␤ (17)...

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Staphlyococcus aureus Phenol-Soluble Modulins Stimulate the Release of Proinflammatory Cytokines from Keratinocytes and Are Required for Induction of Skin Inflammation

et al. 2015

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“…6 Lipoteichoic acid (LTA), another cell wall component of S. aureus, is widely present in AD skin lesions, and its amount detected in the skin correlate with the severity of AD. 7 Although it has long been postulated that superficial infection with S. aureus contributes to AD pathophysiology, the underlying detailed relationship between S. aureus infection and allergic inflammation in AD remains to be addressed.…”

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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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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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“…Our previous study suggested that lipoteichoic acid (LTA), a cell wall component of S. aureus, might amplify skin inflammation in AD [4]. Furthermore, Travers et al have demonstrated the presence of high levels of staphylococcal LTA in AD lesions [5]. However, the relationship between LTA and IL-5 production in patients with AD has not been fully elucidated.…”

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“…Therefore it is likely that Th2 cells in PBMCs from AD patients may have already been primed by intracellular signaling through the T-cell receptor-CD3 surface complex. Since LTA is known to be a ligand for toll-like receptor (TLR) 2 [5], LTA would probably stimulate the TLR2 of antigen-presenting cells (APCs) among PBMCs. This would enhance the expression of CD80/CD86 on APCs and deliver a second signal to the primed Th2 cells through interaction between CD80/CD86 on APCs and CD28 on Th2 cells, resulting in augmentation of IL-5 production.…”

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Lipoteichoic Acid from Staphylococcus aureus Enhances Allergen-Specific IL-5 Production in Patients with Atopic Dermatitis

Matsui¹,

Tofukuji²,

Ikeda³

2017

J Allergy Ther

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The present study investigated the effects of lipoteichoic acid (LTA) derived from Staphylococcus aureus on production of the allergen-specific T helper type 2 (Th2) cytokine, interleukin (IL)-5, in human peripheral blood mononuclear cells (PBMCs) from patients with atopic dermatitis (AD). LTA dose-dependently enhanced the production of allergen-induced IL-5 in PBMCs from patients with AD, but not in those from healthy individuals. Also, when PBMCs from healthy individuals were cultured in a suboptimal concentration of anti-CD3 monoclonal antibody, which alone did not induce IL-5 production, the presence of LTA in the cultures dose-dependently augmented IL-5 production. These results suggest that Th2 cells of AD patients have already been primed by sensitization with various allergens and respond readily to LTA in the presence of an allergen, thus explaining the role of S. aureus colonization in AD patients. . However, the relationship between LTA and IL-5 production in patients with AD has not been fully elucidated. In the present study, therefore, to assess the role of S. aureus colonization in IL-5 production from Th2 cells, the effect of LTA on allergen-specific IL-5 production was investigated using PBMCs from AD patients and healthy individuals.Lymphocytes were isolated as PBMCs from heparinized venous blood from 10 adult patients with AD and 10 age-matched healthy controls. All of the patients had been clinically diagnosed by dermatologists as having AD lesions and had shown positive responses in the skin prick test using house dust mite body extract from Dermatophagoides farinae. None of the subjects had received any systemic or strong topical steroid treatment. The study protocol was approved by the ethics committee of Meiji Pharmaceutical University, and written informed consent for blood sampling was obtained from both the patients and the controls. Cell suspensions containing 2 × 10 6 /mL viable PBMCs in RPMI-1640 with L-glutamine (SigmaAldrich, St. Louis, MO, USA) containing 10% donor-derived serum, 25 mM HEPES buffer (Sigma-Aldrich), 100 U/mL penicillin and 100 μg/mL streptomycin (Gibco RBL, Grand Island, NY, USA) were dispensed into each well of 96-well plates. D. farinae-derived mite antigen (MA) was prepared as described previously [4], and used as an allergen at a final concentration of 10 ng/mL. Highly purified LTA derived from S. aureus was obtained from InvivoGen (Toulouse, France) and used as a stimulant at a final concentration of 0.01-1 μg/mL. The T-lymphocyte mitogenic monoclonal antibody used in this study was mouse anti-human CD3 monoclonal antibody (clone SK7, IgG1 subclass; BD Biosciences, San Jose, CA, USA) and used at a final concentration of 0.5 ng/mL. Cultures were incubated at 37°C in a humidified atmosphere of 5% CO 2 in air. In order to determine the amounts of IL-5 produced, PBMCs were cultured and stimulated as described above. The culture supernatants were collected after incubation for 48 h, and the IL-5 concentrations were measured using ELISA kits for quantificat...

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Infected atopic dermatitis lesions contain pharmacologic amounts of lipoteichoic acid

Abstract: Background-Bacterial infection with Staphylococcus aureus is a known trigger for worsening of atopic dermatitis (AD); the exact mechanisms by which bacterial infection worsens dermatitis are unknown.

Cited by 69 publications

References 34 publications

Staphlyococcus aureus Phenol-Soluble Modulins Stimulate the Release of Proinflammatory Cytokines from Keratinocytes and Are Required for Induction of Skin Inflammation

Staphlyococcus aureus Phenol-Soluble Modulins Stimulate the Release of Proinflammatory Cytokines from Keratinocytes and Are Required for Induction of Skin Inflammation

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

Lipoteichoic Acid from Staphylococcus aureus Enhances Allergen-Specific IL-5 Production in Patients with Atopic Dermatitis

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