Colonization of the skin by Staphylococcus aureus is associated with exacerbation of atopic dermatitis (AD), but any direct mechanism through which dysbiosis of the skin microbiome may influence the development of AD is unknown. Here, we show that proteases and phenol-soluble modulin α (PSMα) secreted by S. aureus lead to endogenous epidermal proteolysis and skin barrier damage that promoted inflammation in mice. We further show that clinical isolates of different coagulase-negative staphylococci (CoNS) species residing on normal skin produced autoinducing peptides that inhibited the S. aureus agr system, in turn decreasing PSMα expression. These autoinducing peptides from skin microbiome CoNS species potently suppressed PSMα expression in S. aureus isolates from subjects with AD without inhibiting S. aureus growth. Metagenomic analysis of the AD skin microbiome revealed that the increase in the relative abundance of S. aureus in patients with active AD correlated with a lower CoNS autoinducing peptides to S. aureus ratio, thus overcoming the peptides’ capacity to inhibit the S. aureus agr system. Characterization of a S. hominis clinical isolate identified an autoinducing peptide (SYNVCGGYF) as a highly potent inhibitor of S. aureus agr activity, capable of preventing S. aureus–mediated epithelial damage and inflammation on murine skin. Together, these findings show how members of the normal human skin microbiome can contribute to epithelial barrier homeostasis by using quorum sensing to inhibit S. aureus toxin production.

Atopic dermatitis (AD) is a common skin disease that affects a large proportion of the population worldwide. The incidence of AD has increased over the last several decades along with AD's burden on the physical and psychological health of the patient and family. However, current advances in understanding the mechanisms behind the pathophysiology of AD are leading to a hopeful outlook for the future. Staphylococcus aureus (S. aureus) colonization on AD skin has been directly correlated to disease severity but the functions of other members of the skin bacterial community may be equally important. Applying knowledge gained from understanding the role of the skin microbiome in maintaining normal skin immune function, and addressing the detrimental consequences of microbial dysbiosis in driving inflammation, is a promising direction for development of new treatments. This review discusses current preclinical and clinical research focused on determining how the skin microbiome may influence the development of AD.

SUMMARY Type 1 interferons (IFN) promote inflammation in the skin but the mechanisms responsible for inducing these cytokines are not well understood. We found that IFNβ was abundantly produced by epidermal keratinocytes (KCs) in psoriasis and during wound repair. KC IFNβ production depended on stimulation of mitochondrial antiviral-signaling protein (MAVS) by the antimicrobial peptide LL37 and double stranded-RNA released from necrotic cells. MAVS activated downstream TBK1 (TANK-Binding Kinase 1)-AKT (AKT serine/threonine kinase 1)-IRF3 (interferon regulatory factor 3) signaling cascade leading to IFNβ production, and then promoted maturation of dendritic cells. In mice, the production of epidermal IFNβ by LL37 required MAVS, and human wounded and/or psoriatic skin showed activation of MAVS-associated IRF3 and induction of MAVS and IFNβ gene signatures. These findings show that KCs are an important source of IFNβ and MAVS is critical to this function, and demonstrates how the epidermis triggers unwanted skin inflammation under disease conditions.

Epidermal keratinocytes participate in immune defense through their capacity to recognize danger, trigger inflammation, and resist infection. However, normal skin immune function must tolerate contact with an abundant community of commensal microbes without inflammation. We hypothesized that microbial environmental conditions dictate the production of molecules that influence epigenetic events and cause keratinocytes to break innate immune tolerance. , a commensal skin bacterium, produced the short-chain fatty acids (SCFAs) propionate and valerate when provided a lipid source in hypoxic growth conditions, and these SCFAs inhibited histone deacetylase (HDAC) activity. Inhibition of HDAC activity in keratinocytes promoted cytokine expression in response to Toll-like receptor (TLR) ligands for TLR2 or TLR3. This response was opposite to the action of HDAC inhibition on production of inflammatory cytokines by monocytes and involved HDAC8 and HDAC9 because small interfering RNA silencing of these HDACs recapitulated the activity of SCFAs. Analysis of cytokine expression in mice confirmed the response of the epidermis where application of SCFA on the skin surface promoted cytokine expression, whereas subcutaneous administration was inhibitory. These findings show that the products of commensal microbes made under specific conditions will inhibit HDAC activity and break tolerance of the epidermis to inflammatory stimuli.

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.