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Allergic diseases have in common a dysfunctional epithelial barrier, which allows the penetration of allergens and microbes, leading to the release of type 2 cytokines that drive allergic inflammation. The accessibility of skin, compared with lung or gastrointestinal tissue, has facilitated detailed investigations into mechanisms underlying epithelial barrier dysfunction in atopic dermatitis (AD). This Review describes the formation of the skin barrier and analyzes the link between altered skin barrier formation and the pathogenesis of AD. The keratinocyte differentiation process is under tight regulation. During epidermal differentiation, keratinocytes sequentially switch gene expression programs, resulting in terminal differentiation and the formation of a mature stratum corneum, which is essential for the skin to prevent allergen or microbial invasion. Abnormalities in keratinocyte differentiation in AD skin result in hyperproliferation of the basal layer of epidermis, inhibition of markers of terminal differentiation, and barrier lipid abnormalities, compromising skin barrier and antimicrobial function. There is also compelling evidence for epithelial dysregulation in asthma, food allergy, eosinophilic esophagitis, and allergic rhinosinusitis. This Review examines current epithelial barrier repair strategies as an approach for allergy prevention or intervention.

Staphylococcus aureus colonizes patients with atopic dermatitis (AD) and exacerbates disease by promoting inflammation. The present study investigated the safety and mechanisms of action of Staphylococcus hominis A9 ( Sh A9), a bacterium isolated from healthy human skin, as a topical therapy for AD. Sh A9 killed S. aureus on the skin of mice and inhibited expression of a toxin from S. aureus ( psm α) that promotes inflammation. A first-in-human, phase 1, double-blinded, randomized 1-week trial of topical Sh A9 or vehicle on the forearm skin of 54 adults with S. aureus -positive AD (NCT03151148) met its primary endpoint of safety, and participants receiving Sh A9 had fewer adverse events associated with AD. Eczema severity was not significantly different when evaluated in all participants treated with Sh A9 but a significant decrease in S. aureus and increased Sh A9 DNA were seen and met secondary endpoints. Some S. aureus strains on participants were not directly killed by Sh A9, but expression of mRNA for psm α was inhibited in all strains. Improvement in local eczema severity was suggested by post-hoc analysis of participants with S. aureus directly killed by Sh A9. These observations demonstrate the safety and potential benefits of bacteriotherapy for AD. First-in-human test of topical application of a commensal bacterium on skin of individuals with atopic dermatitis reduces colonization by proinflammatory Staphylococcus aureus .

Mutations in the filaggrin gene are associated with a broad range of skin and allergic diseases. The biology of this molecule and the role of mutations in its altered function offer new insights into a range of conditions not previously thought to be related to one another. Mutations in the filaggrin gene ( FLG ) are among the most common and profound single-gene defects identified to date in the causation and modification of disease. FLG encodes an important epidermal protein abundantly expressed in the outer layers of the epidermis. 1 Approximately 10% of persons of European ancestry are heterozygous carriers of a loss-of-function mutation in FLG, resulting in a 50% reduction in expressed protein. 2 The critical role of filaggrin in epidermal function underlies the pathogenic importance of this gene in common dermatologic and allergic diseases. The spectrum of such diseases encompasses monogenic disorders of keratinization through complex abnormalities . . .

Atopic dermatitis (AD) is an inflammatory skin disease characterized by increased T-helper type 2 (Th2) cytokine expression. AD skin lesions are often exacerbated by Staphylococcus aureus–mediated secretion of the lytic virulence factor, alpha toxin. In the current study, we report that alpha toxin–induced cell death is greater in the skin from patients with AD compared with controls. Furthermore, we find that keratinocyte differentiation and Th2 cytokine exposure influence sensitivity to S. aureus alpha toxin–induced cell death. Differentiated keratinocytes are protected from cell death, whereas cells treated with Th2 cytokines have increased sensitivity to alpha toxin–induced lethality. Our data demonstrate that the downstream effects mediated by Th2 cytokines are dependent upon host expression of STAT6. We determine that Th2 cytokines induce biochemical changes that decrease levels of acid sphingomyelinase (SMase), an enzyme that cleaves sphingomyelin, an alpha toxin receptor. Furthermore, Th2 cytokines inhibit the production of lamellar bodies, organelles critical for epidermal barrier formation. Finally, we determine that SMase and its enzymatic product, phosphocholine, prevent Th2-mediated increases in alpha toxin–induced cell death. Therefore, our studies may help explain the increased propensity for Th2 cytokines to exacerbate S. aureus–induced skin disease, and provide a potential therapeutic target for treatment of AD.

The molecular mechanisms that underlie the detrimental effects of particulate matter (PM) on skin barrier function are poorly understood. In this study, the effects of PM2.5 on filaggrin (FLG) and skin barrier function were investigated in vitro and in vivo. The levels of FLG degradation products, including pyrrolidone carboxylic acid, urocanic acid (UCA), and cis/trans-UCA, were significantly decreased in skin tape stripping samples of study subjects when they moved from Denver, an area with low PM2.5, to Seoul, an area with high PM2.5 count. Experimentally, PM2.5 collected in Seoul inhibited FLG, loricrin, keratin-1, desmocollin-1, and corneodesmosin but did not modulate involucrin or claudin-1 in keratinocyte cultures. Moreover, FLG protein expression was inhibited in human skin equivalents and murine skin treated with PM2.5. We demonstrate that this process was mediated by PM2.5-induced TNF-α and was aryl hydrocarbon receptor dependent. PM2.5 exposure compromised skin barrier function, resulting in increased transepidermal water loss, and enhanced the penetration of FITC-dextran in organotypic and mouse skin. PM2.5-induced TNF-α caused FLG deficiency in the skin and subsequently induced skin barrier dysfunction. Compromised skin barrier due to PM2.5 exposure may contribute to the development and the exacerbation of allergic diseases such as atopic dermatitis.

Staphylococcal infections of the skin are more common in patients with atopic dermatitis than they are in normal persons or patients with psoriasis. In this study, the investigators hypothesized that the elevated rate of skin infections in atopic dermatitis could be attributed to reduced levels of the endogenous antimicrobial peptides LL-37 and human β-defensin 2. They found that the levels of these peptides were lower in skin from patients with atopic dermatitis. The skin's first line of defense against invasion by microbial agents is the stratum corneum, a nonviable, desiccated layer of the epidermis. 1 However, this physical barrier is susceptible to injuries that allow the entry of opportunistic microbial agents into the skin. The innate immune system can immediately respond to this intrusion by helping to prevent further invasion. This immune response includes phagocytosis by neutrophils and macrophages and their production of reactive oxygen intermediates that kill microbial agents. 2 A number of endogenous antimicrobial peptides have been shown to play an integral part in innate immunity. 3 Two major classes of peptides in . . .

Atopic dermatitis (AD) is an inflammatory skin disease associated with frequent skin infection and impaired skin barrier function. Recent studies indicate that increased Th2 cytokine expression contributes to reduction in antimicrobial peptides and reduced filaggrin (FLG) expression, however, the mechanisms leading to this effect is unknown. Using proteomics, we found the S100 calcium-binding protein A11 (S100/A11) to be significantly downregulated in the presence of IL-4 and IL-13. Culturing keratinocytes with increased calcium concentrations significantly induced S100/A11 expression. This corresponded with an increase in human β-defensin (HBD)-3 and FLG expression. Interference of S100/A11 expression, by siRNA, inhibited induction of HBD-3 and FLG. Furthermore p21, a cyclin-dependent kinase inhibitor downstream of S100/A11, was required for calcium-mediated induction of HBD-3 and FLG. Importantly, transduction of p21-recombinant protein into keratinocytes prevented IL-4/IL-13-mediated inhibition of FLG and HBD-3 expression. S100/A11 and p21 gene expression was also found to be significantly lower in acute and chronic AD skin. This study demonstrates an important role for S100/A11 and p21 in regulating skin barrier integrity and the innate immune response.

Type I interferon kappa (IFNκ) is selectively expressed in human keratinocytes. Herpes simplex virus-1 (HSV-1) is a human pathogen that infects keratinocytes and causes lytic skin lesions. Whether IFNκ plays a role in keratinocyte host defense against HSV-1 has not been investigated. In this study, we found that IFNκ mRNA expression was induced by addition of recombinant IFNκ and poly (I:C); and its expression level was significantly greater than IFNa2, IFNb1, and IFNL1 in both undifferentiated and differentiated normal human epidermal keratinocytes (NHEKs) under resting and stimulation conditions. Although IFNe was expressed at a relatively higher level than other IFNs in resting undifferentiated NHEK, its expression level did not change after stimulation with recombinant IFNκ and poly (I:C). HSV-1 infection inhibited gene expression of IFNκ and IFNe in NHEK. Silencing IFNκ in NHEK led to significantly enhanced HSV-1 replication in both undifferentiated and differentiated NHEK compared to scrambled siRNA-transfected cells, while the addition of recombinant IFNκ significantly reduced HSV-1 replication in NHEK. In addition, we found that IFNκ did not regulate protein expression of NHEK differentiation markers. Our results demonstrate that IFNκ is the dominant type of IFNs in keratinocytes and it has an important function for keratinocytes to combat HSV-1 infection.

Injections of TNX-901 may provide protection after ingestion of peanut. Peanut allergy is characterized by symptoms and signs after ingestion that may include nausea, vomiting, diarrhea, abdominal pain, urticaria, angioedema, bronchospasm, hypotension, loss of consciousness, and death. 1 , 2 Although data from animals demonstrate that allergic reactions are mediated by antigen-specific IgE bound to high-affinity receptors for IgE (FcεRIs) on mast cells and basophils, 3 , 4 non-IgE pathways for anaphylaxis exist, at least in mice, 5 , 6 and direct clinical evidence of IgE involvement in peanut allergy in humans is lacking. Approximately 1.5 million people in the United States have peanut allergy, 7 , 8 50 to 100 of whom die each year from unintended . . .