Epithelial keratinocyte proliferation is an essential element of wound repair, and abnormal epithelial proliferation is an intrinsic element in the skin disorder psoriasis. The factors that trigger ...epithelial proliferation in these inflammatory processes are incompletely understood. Here we have shown that regenerating islet-derived protein 3-alpha (REG3A) is highly expressed in keratinocytes during psoriasis and wound repair and in imiquimod-induced psoriatic skin lesions. The expression of REG3A by keratinocytes is induced by interleukin-17 (IL-17) via activation of keratinocyte-encoded IL-17 receptor A (IL-17RA) and feeds back on keratinocytes to inhibit terminal differentiation and increase cell proliferation by binding to exostosin-like 3 (EXTL3) followed by activation of phosphatidylinositol 3 kinase (PI3K) and the kinase AKT. These findings reveal that REG3A, a secreted intestinal antimicrobial protein, can promote skin keratinocyte proliferation and can be induced by IL-17. This observation suggests that REG3A may mediate the epidermal hyperproliferation observed in normal wound repair and in psoriasis.
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► REG3A is abundantly expressed in psoriasis and skin wounds ► IL-17 induces REG3A in epidermal keratinocytes ► REG3A induces keratinocyte proliferation but inhibits its differentiation ► REG3A activates EXTL3-PI3K-Akt to promote wound healing
Rosacea is a chronic inflammatory skin condition that affects approximately 16 million Americans. Four distinct subtypes of rosacea have been recognized, with transient and nontransient facial ...flushing, telangiectasia, and inflammatory papules and pustules being among the more commonly recognized features. Although the exact pathogenesis of rosacea is unknown, dysregulation of the innate immune system, overgrowth of commensal skin organisms, and aberrant neurovascular signaling may all have a role in promoting the clinical features of rosacea.
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 (ShA9), a bacterium isolated from healthy human skin, as a topical therapy for AD. ShA9 killed S. aureus on the skin of mice and inhibited expression of a toxin from S. aureus (psmα) that promotes inflammation. A first-in-human, phase 1, double-blinded, randomized 1-week trial of topical ShA9 or vehicle on the forearm skin of 54 adults with S. aureus-positive AD (NCT03151148) met its primary endpoint of safety, and participants receiving ShA9 had fewer adverse events associated with AD. Eczema severity was not significantly different when evaluated in all participants treated with ShA9 but a significant decrease in S. aureus and increased ShA9 DNA were seen and met secondary endpoints. Some S. aureus strains on participants were not directly killed by ShA9, but expression of mRNA for psmα was inhibited in all strains. Improvement in local eczema severity was suggested by post-hoc analysis of participants with S. aureus directly killed by ShA9. These observations demonstrate the safety and potential benefits of bacteriotherapy for AD.
Patients with atopic dermatitis (AD) have an abnormal skin barrier and are frequently colonized by S. aureus. In this study we investigated if S. aureus penetrates the epidermal barrier of subjects ...with AD and sought to understand the mechanism and functional significance of this entry. S. aureus was observed to be more abundant in the dermis of lesional skin from AD patients. Bacterial entry past the epidermis was observed in cultured human skin equivalents and in mice but was found to be increased in the skin of cathelicidin knockout and ovalbumin-sensitized filaggrin mutant mice. S. aureus penetration through the epidermis was dependent on bacterial viability and protease activity, because killed bacteria and a protease-null mutant strain of S. aureus were unable to penetrate. Entry of S. aureus directly correlated with increased expression of IL-4, IL-13, IL-22, thymic stromal lymphopoietin, and other cytokines associated with AD and with decreased expression of cathelicidin. These data illustrate how abnormalities of the epidermal barrier in AD can alter the balance of S. aureus entry into the dermis and provide an explanation for how such dermal dysbiosis results in increased inflammatory cytokines and exacerbation of disease.
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
, 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
was performed on isolates of coagulase-negative
(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
The antimicrobial activity was identified as previously unknown antimicrobial peptides (AMPs) produced by CoNS species including
and
These AMPs were strain-specific, highly potent, selectively killed
, 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
These findings show how commensal skin bacteria protect against pathogens and demonstrate how dysbiosis of the skin microbiome can lead to disease.
Staphylococcus aureus and Staphylococcus epidermidis are the most abundant bacteria found on the skin of patients with atopic dermatitis (AD). S aureus is known to exacerbate AD, whereas S ...epidermidis has been considered a beneficial commensal organism.
In this study, we hypothesized that S epidermidis could promote skin damage in AD by the production of a protease that damages the epidermal barrier.
The protease activity of S epidermidis isolates was compared with that of other staphylococcal species. The capacity of S epidermidis to degrade the barrier and induce inflammation was examined by using human keratinocyte tissue culture and mouse models. Skin swabs from atopic and healthy adult subjects were analyzed for the presence of S epidermidis genomic DNA and mRNA.
S epidermidis strains were observed to produce strong cysteine protease activity when grown at high density. The enzyme responsible for this activity was identified as EcpA, a cysteine protease under quorum sensing control. EcpA was shown to degrade desmoglein-1 and LL-37 in vitro, disrupt the physical barrier, and induce skin inflammation in mice. The abundance of S epidermidis and expression of ecpA mRNA were increased on the skin of some patients with AD, and this correlated with disease severity. Another commensal skin bacterial species, Staphylococcus hominis, can inhibit EcpA production by S epidermidis.
S epidermidis has commonly been regarded as a beneficial skin microbe, whereas S aureus has been considered deleterious. This study suggests that the overabundance of S epidermidis found on some atopic patients can act similarly to S aureus and damage the skin by expression of a cysteine protease.
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Although rosacea's impact on physical health is limited, it has profound effects on a person's psychological well-being. Therefore, treating rosacea can greatly affect a person's quality of life. ...Patient education regarding trigger avoidance and skin care techniques such as moisturizing and sun protection are important non-pharmacologic first steps in treating rosacea. Pharmacologic interventions range from topical to systemic medications, with the ideal medication choice dependent on the symptoms and severity of each individual patient. Despite this variety of therapeutic options, none of these therapies are completely curative, and therefore further research into the pathophysiology of rosacea is required in order to create more targeted and efficacious treatment options.
To the Editor: Atopic dermatitis (AD) is a chronic skin condition that affects 10% to 20% of children and 1% to 3% of adults.1 Individuals with atopic dermatitis are at an increased risk for ...cutaneous infections with Staphylococcus aureus, herpes simplex, and the small pox or vaccinia virus.2 Recently, it has been shown that defects in the innate immune system, such as the capacity to increase the production of broad spectrum antimicrobial peptides like cathelicidin, may account for this increase in infections.3,4 Important insight into the mechanism responsible for the production of antimicrobial peptides came with the discovery of the vitamin D response element in the cathelicidin promoter and the finding that the conversion of 25-hydroxyvitamin D to the active 1,25 dihydroxyvitamin D by CYP27B1 can occur in keratinocytes and monocytes and is under the control of Toll-like receptor 2.4-6 Thus, with infection or wounding, activation of Toll-like receptor 2 results in expression of CYP27B1, causing conversion of 25-hydroxyvitamin D to the active 1,25 dihydroxyvitamin D, and subsequent induction of cathelicidin.5,6 Our study sought to examine whether supplementation with oral cholecalciferol could provide the CYP27B1 enzyme enough substrate to overcome this relative deficiency in induction of cathelicidin in atopic patients. Because this increase is primarily seen in lesional skin, it is hypothesized that only with the supplementation with oral vitamin D can AD lesional skin be allowed to increase cathelicidin to its normal level seen postinjury.
Atopic dermatitis (AD) is a chronic inflammatory skin disease. Here, we show that phospholipase C-β3 (PLC-β3)-deficient mice spontaneously develop AD-like skin lesions and more severe ...allergen-induced dermatitis than wild-type mice. Mast cells were required for both AD models and remarkably increased in the skin of Plcb3−/− mice because of the increased Stat5 and reduced SHP-1 activities. Mast cell-specific deletion of Stat5 gene ameliorated allergen-induced dermatitis, whereas that of Shp1 gene encoding Stat5-inactivating SHP-1 exacerbated it. PLC-β3 regulates the expression of periostin in fibroblasts and TSLP in keratinocytes, two proteins critically involved in AD pathogenesis. Furthermore, polymorphisms in PLCB3, SHP1, STAT5A, and STAT5B genes were associated with human AD. Mast cell expression of PLC-β3 was inversely correlated with that of phospho-STAT5, and increased mast cells with high levels of phospho-STAT5 were found in lesional skin of some AD patients. Therefore, STAT5 regulatory mechanisms in mast cells are important for AD pathogenesis.
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•PLCb3−/− mice develop AD spontaneously and severe allergen-induced dermatitis•Stat5-dependent mast cells were increased and required for both AD models•PLC-β3 represses expression of periostin in fibroblasts and TSLP in keratinocytes•Mast cells with high nuclear phospho-STAT5 were found in lesions of AD patients
Atopic dermatitis (AD) is a common inflammatory skin disease. In this study, Kawakami and colleagues show that phospholipase C-β3 (PLC-β3)-deficient mice develop AD-like skin lesions in a mast cell-dependent manner. Mast cells in the skin of Plcb3−/− mice were increased by elevated STAT5 activity. Mast cell expression of PLC-β3 was inversely correlated with that of phospho-STAT5, and skin mast cells with high phospho-STAT5 were found in some patients. Therefore, STAT5 regulation in mast cells is important for AD pathogenesis.
During inflammation, the skin deploys antimicrobial peptides (AMPs) yet during allergic inflammation it becomes more susceptible to Staphylococcus aureus. To understand this contradiction, ...single-cell sequencing of Il4ra−/− mice combined with skin microbiome analysis reveals that lower production of AMPs from interleukin-4 receptor α (IL-4Rα) activation selectively inhibits survival of antibiotic-producing strains of coagulase-negative Staphylococcus (CoNS). Diminished AMPs under conditions of T helper type 2 (Th2) inflammation enable expansion of CoNS strains without antibiotic activity and increase Staphylococcus aureus (S. aureus), recapitulating the microbiome on humans with atopic dermatitis. This response is rescued in Camp−/− mice or after topical steroids, since further inhibition of AMPs enables survival of antibiotic-producing CoNS strains. In conditions of Th17 inflammation, a higher expression of host AMPs is sufficient to directly inhibit S. aureus survival. These results show that antimicrobials produced by the host and commensal bacteria each act to control S. aureus on the skin.
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•Skin colonization by Staphylococcus aureus exacerbates existing Th2 inflammation•IL-4Rα suppresses but does not eliminate antimicrobial peptide (AMP) expression•CoNS that express antibiotics are more sensitive to AMPs than S. aureus or other CoNS•Loss of antimicrobial defense from AMPs and CoNS enables S. aureus survival on skin
Nakatsuji et al. report how activation of IL-4Rα partially suppresses production of antimicrobial peptides from the skin so that they cannot kill Staphylococcus aureus (S. aureus) but do inhibit protective strains of Staphylococcus that produce bacteriocins. Their findings can explain why S. aureus expands on the skin of patients with atopic dermatitis.
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