Staphylococcus aureus Exploits Epidermal Barrier Defects in Atopic Dermatitis to Trigger Cytokine Expression

Nakatsuji, Teruaki; Chen, Tiffany H.; Two, Aimee M.; Chun, Kimberly; Narala, Saisindhu; Geha, Raif S.; Hata, Tissa; Gallo, Richard L.

doi:10.1016/j.jid.2016.05.127

Cited by 294 publications

(292 citation statements)

References 63 publications

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“…However, in mice where tissue stress is induced by contact hypersensitivity to DNFB, S. xylosus exacerbated the inflammatory response, assessed by increased recruitment of neutrophils and upregulated expression of IL-1β. These results are consistent with other studies showing that mice with barrier defects allow Staphylococcus to penetrate the epidermal barrier and subsequently increase cytokine expression in the skin (Nakatsuji et al, 2016). In some situations the cytokine production may be protective, such as during a fungal infection (Naik et al, 2015).…”

Section: Discussionsupporting

confidence: 93%

Cutaneous Leishmaniasis Induces a Transmissible Dysbiotic Skin Microbiota that Promotes Skin Inflammation

Gimblet

Meisel

Loesche

et al. 2017

Cell Host & Microbe

100

113

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Summary Skin microbiota can impact allergic and autoimmune responses, wound healing and anti-microbial defense. We investigated the role of skin microbiota in cutaneous leishmaniasis and found that human patients infected with Leishmania braziliensis develop dysbiotic skin microbiota, characterized by increases in the abundance of Staphylococcus and/or Streptococcus. Mice infected with L. major exhibit similar changes depending upon disease severity. Importantly, this dysbiosis is not limited to the lesion site, but is transmissible to normal skin distant from the infection site, and to skin from co-housed naïve mice. This observation allowed us to test whether a preexisting dysbiotic skin microbiota influences disease, and we found that challenging dysbiotic naïve mice with L. major or testing for contact hypersensitivity results in exacerbated skin inflammatory responses. These findings demonstrate that a dysbiotic skin microbiota is not only a consequence of tissue stress, but also enhances inflammation, which has implications for many inflammatory cutaneous diseases.

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Section: Discussionsupporting

confidence: 93%

Cutaneous Leishmaniasis Induces a Transmissible Dysbiotic Skin Microbiota that Promotes Skin Inflammation

Gimblet

Meisel

Loesche

et al. 2017

Cell Host & Microbe

100

113

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“…Our whole tissue zymograms (Figure 3) demonstrated that the casein substrate was degraded at sites other than the epidermis. Since bacteria including S. aureus can penetrate the skin surface and elicit strong dermal immune responses (Nakatsuji et al , 2016; Nakatsuji et al , 2013; Zhang et al , 2015), it is possible these bacteria may also influence protease activity of dermal cells. It will be interesting to see if changes in skin protease activity are also dependent on skin barrier penetration by S. aureus .…”

Section: Discussionmentioning

confidence: 99%

“…The resulting increase in enzymatic activity leads to increased desquamation, altered antimicrobial peptide (AMP) and filaggrin (FLG) processing, and PAR-2 activation and inflammation (Borgono et al , 2007; Caubet et al , 2004; Sakabe et al , 2013; Stefansson et al , 2008). Increased protease activity may also play an important role in the communication of the microbiome with the skin immune system, and has recently been shown to directly influence epidermal cytokine production and inflammation by enhancing penetration of bacteria through the epidermis (Nakatsuji et al , 2016). …”

Section: Introductionmentioning

confidence: 99%

Staphylococcus aureus Induces Increased Serine Protease Activity in Keratinocytes

Williams

Nakatsuji

Sanford

et al. 2017

Journal of Investigative Dermatology

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133

106

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Bacteria that reside on the skin can influence the behavior of the cutaneous immune system, but the mechanisms responsible for these effects are incompletely understood. Colonization of the skin by Staphylococcus aureus (S. aureus) is increased in atopic dermatitis (AD) and can result in increased severity of the disease. In this study we show that S. aureus stimulates human keratinocytes to increase their endogenous protease activity, including specific increases in trypsin activity. This increased protease activity coincided with increased expression of mRNA for kallikreins (KLKs), with KLK6, 13, and 14 showing the greatest induction after exposure to S. aureus. Suppression of mRNA for these KLKs in keratinocytes by targeted siRNA silencing prior to S. aureus exposure blocked the increase in protease activity. Keratinocytes exposed to S. aureus showed enhanced degradation of desmoglein-1 (DSG-1) and filaggrin (FLG) while siRNA for KLK6, KLK13, and KLK14 partially blocked this degradation. These data illustrate how S. aureus directly influences the skin barrier integrity by stimulating endogenous proteolytic activity and defines a previously unknown mechanism by which S. aureus may influence skin diseases.

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“…Mice develop AD-like lesions when they are experimentally colonized by S.aureus (19, 20). However, in contrast to the exacerbation of disease and inflammation caused by S.aureus , other bacterial species found on normal skin appear to aid in normal immune homeostasis (21).…”

Section: Introductionmentioning

confidence: 99%

Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis

et al. 2017

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The microbiome can promote or disrupt human health by influencing both adaptive and innate immune functions. We tested whether bacteria that normally reside on human skin participate in host defense by killing Staphylococcus aureus, a pathogen commonly found in patients with atopic dermatitis (AD) and an important factor that exacerbates this disease. High-throughput screening for antimicrobial activity against S.aureus was performed on isolates of coagulase-negative Staphylococcus (CoNS) collected from the skin of healthy and AD subjects. CoNS strains with antimicrobial activity were common on the normal population but rare on AD subjects. A low frequency of strains with antimicrobial activity correlated with colonization by S.aureus. The antimicrobial activity was identified as previously unknown antimicrobial peptides (AMPs) produced by CoNS species including Staphylococcus epidermidis and Staphylococcus hominis. These AMPs were strain-specific, highly potent, selectively killed S.aureus, and synergized with the human AMP LL-37. Application of these CoNS strains to mice confirmed their defense function in vivo relative to application of nonactive strains. Strikingly, reintroduction of antimicrobial CoNS strains to human subjects with AD decreased colonization by S.aureus. These findings show how commensal skin bacteria protect against pathogens and demonstrate how dysbiosis of the skin microbiome can lead to disease.

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Staphylococcus aureus Exploits Epidermal Barrier Defects in Atopic Dermatitis to Trigger Cytokine Expression

Cited by 294 publications

References 63 publications

Cutaneous Leishmaniasis Induces a Transmissible Dysbiotic Skin Microbiota that Promotes Skin Inflammation

Cutaneous Leishmaniasis Induces a Transmissible Dysbiotic Skin Microbiota that Promotes Skin Inflammation

Staphylococcus aureus Induces Increased Serine Protease Activity in Keratinocytes

Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis

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