Loss Of Skin Barrier Function Research Articles

Mechanisms for initiation of food allergy by skin pre-disposed to atopic dermatitis.

Food allergy can be life-threatening and often develops early in life. In infants and children, loss-of-function mutations in skin barrier genes associate with food allergy. In a mouse model with skin barrier mutations (Flakey Tail, FT+/- mice), topical epicutaneous sensitization to a food allergen peanut extract (PNE), an environmental allergen Alternaria alternata (Alt) and a detergent induce food allergy and then an oral PNE-challenge induces anaphylaxis. Exposures to these allergens and detergents can occur for infants and children in a household setting. From the clinical and preclinical studies of neonates and children with skin barrier mutations, early oral exposure to allergenic foods before skin sensitization may induce tolerance to food allergens and thus protect against development of food allergy. In the FT+/- mice, oral food allergen prior to skin sensitization induce tolerance to food allergens. However, when the skin of FT+/- pups are exposed to a ubiquitous environmental allergen at the time of oral consumption of food allergens, this blocks the induction of tolerance to the food allergen and the mice can then be skin sensitized with the food allergen. The development of food allergy in neonatal FT+/- mice is mediated by altered skin responses to allergens with increases in skin expression of interleukin 33, oncostatin M and amphiregulin. The development of neonate food allergy is enhanced when born to an allergic mother, but it is inhibited by maternal supplementation with α-tocopherol. Moreover, preclinical studies suggest that food allergen skin sensitization can occur before manifestation of clinical features of atopic dermatitis. Thus, these parameters may impact design of clinical studies for food allergy, when stratifying individuals by loss of skin barrier function or maternal atopy before offspring development of atopic dermatitis.

The Riddle of Cetuximab-Related Skin Toxicity: 1H-NMR Sebum Analysis Revealed Dynamic Lipid Alterations Associated with Skin Toxicity Development in Metastatic Colorectal Cancer Patients.

The epidermal growth factor receptor inhibitor (EGFRIs) treatments are commonly associated with the development of adverse skin effects. This study aims to investigate the lipid composition change in sebum during cetuximab-based treatment in an attempt to identify specific metabolic signatures useful in predicting the occurrence of severe skin toxicity. Sebum from 30 metastatic colorectal cancer (mCRC) patients was collected at three time points during the targeted therapy by the application of Sebutape® on the forehead, and the major lipid classes were analyzed and quantified by 1H-NMR. Univariate analysis was performed to reveal significant alterations among patients in sebum production as well as lipid composition and over the course of cetuximab therapy. A transient but significant decrease in sebum production associated with a reduction in the relative content of triglycerides (TG) and squalene (SQ) was found to be induced by cetuximab administration. The reduction of these two lipid classes was also found to be associated with the severity of skin rash experienced by patients. The results of this study indicate that cetuximab-based treatment can reduce sebum gland activity, leading to an overall decrease in sebum production and the induction of specific modifications to its composition. The extent of the loss of skin barrier function may be important for determining the severity of skin toxicity development.

Epidemiological retrospective analysis in major burn patients: single centre medical records from 2009 to 2019.

Burns cause a loss of skin barrier function, rendering it prone to infection. The prevention of infection comprises a focus on the treatment of patients with burns. Therefore, we analysed the results of microbiological tests of patients with severe and extremely severe burns to provide a basis for the prevention and treatment of infection in patients with burns. The results of microbiological tests of patients with severe and extremely severe burns admitted to our burn centre between 2009 and 2019 were retrospectively reviewed. The overall positive rate of microbial detection was 40.67% and did not significantly decline over the 10-year study period. The most common positive sites were wounds, sputum, and urine. The most common bacterial species causing the infections were Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Furthermore, the predictors of a positive detection, overall and at various sites, mainly included the burn area and depth, inhalation injury, and length of the hospital stay. Positive detection was an important predictor of the prognosis. In particular, a positive blood culture and Klebsiella pneumoniae had better predictive strength for mortality than other sites and strains. This study analysed the microbiological testing results at a single burn centre over a period of 10years. The results provide information regarding the predictors of a positive detection and the influence of a positive detection on prognosis, and can be used as a basis for the development of clinical infection prevention and treatment strategies, as well as the selection of treatment measures.

Protective and Anti-Aging Effects of 5 Cosmeceutical Peptide Mixtures on Hydrogen Peroxide-Induced Premature Senescence in Human Skin Fibroblasts

Skin aging usually leads to the excessive deterioration of the dermal extracellular matrix, loss of antimicrobial function, loss of skin barrier function, and a series of inflammatory processes. Bioactive peptides have been widely used in cosmetics due to their protective effects on skin and efficient absorption. Combination of different peptides may lead to synergistic or antagonistic effects, so different formulas need to be designed and tested properly. In this study, 5 functional cosmeceutical peptides were tested on their individual and mixed activities to detect a suitable anti-aging and protective formula from our experiments. After the individual activity test, the optimal concentration is 200 μg/mL of carnosine for the superoxide dismutase (SOD) activity, 200 μg/mL of GHK peptide for the hydroxyproline (HYP) content activity, 100 μg/mL of acetyl tetrapeptide-5 for the angiotensin-converting enzyme 1 activity, 400 μg/mL of hexapeptide-11 for the HYP content activity, and 400 μg/mL of acetyl hexapeptide-3 for the catecholamine content activity. According to the optimal concentration of these 5 cosmeceutical peptides, 6 formulations of peptide mixtures were designed and tested for their anti-aging activities and protective effects against hydrogen peroxide-induced premature senescence in human skin fibroblasts. One of the cosmeceutical peptide mixtures (carnosine + acetyl tetrapeptide-5 + hexapeptide-11 + acetyl hexapeptide-3) significantly reduced the intracellular malondialdehyde and hydroxyl free radical contents and increased the HYP and human elastin contents as well as the enzymatic activities of SOD and glutathione peroxidase. Our study suggests that this formula of cosmeceutical peptide mixtures could be a promising agent for use in anti-aging and protective cosmetics.

Topical Aminosalicylic Acid Improves Keratinocyte Differentiation in an Inducible Mouse Model of Harlequin Ichthyosis

SummaryMutations in the lipid transport protein ABCA12 cause the life-threatening skin condition harlequin ichthyosis (HI), which is characterized by the loss of skin barrier function, inflammation, and dehydration. Inflammatory responses in HI increase disease severity by impairing keratinocyte differentiation, suggesting amelioration of this phenotype as a possible therapy for the condition. Existing treatments for HI are based around the use of retinoids, but their value in treating patients during the neonatal period has been questioned relative to other improved management regimens, and their long-term use is associated with side effects. We have developed a conditional mouse model to demonstrate that topical application of the aminosalicylic acid derivatives 5ASA or 4ASA considerably improves HI keratinocyte differentiation without the undesirable side effects of the retinoid acitretin and salicylic acid (aspirin). Analysis of changes in gene expression shows that 4ASA in particular elicits compensatory upregulation of a large family of barrier function-related genes, many of which are associated with other ichthyoses, identifying this compound as a lead candidate for developing topical treatments for HI.

Epidemiology, prevalence and risk factors for infections in burn patients: results from a regional burn centre’s analysis

Burn patients are at high risk of infections due to severe impairment of immunity and loss of skin barrier function. We aimed to describe the epidemiology, incidence and risk factors for infection in a cohort of burns patients. Two hundred patients were retrospectively enrolled and subdivided into infected (N = 81) and uninfected groups (N = 119). The cumulative prevalence of infections was 27% on day 7 and 43.8% on day 28. Skin and soft tissue infections (32%) were the most frequent. Carbapenem-resistant Acinetobacter baumannii (28%), Pseudomonas aeruginosa (26%) and methicillin-resistant Staphylococcus aureus (25%) infections were most prevalent. An indwelling central venous catheter (CVC; sub-hazard ratio [SHR] 7.41, 95% confidence interval [CI] 3.78–14.62) and revised Baux score (RBS; SHR 2.08, 95% CI 0.98–4.42) were associated with higher incremental infection rate while surgical treatment resulted in a protective factor (SHR 0.45, 95% CI 0.29–0.75). RBS may be useful to stratify the infection risk: a strict collaboration between surgeons and infectious disease specialists is needed to implement source control and antimicrobial surveillance.

Spontaneous atopic dermatitis in mice with a defective skin barrier is independent of ILC2 and mediated by IL-1β.

BackgroundAtopic dermatitis (AD) is one of the most common skin diseases with a multifactorial etiology. Mutations leading to loss of skin barrier function are associated with the development of AD with group 2 innate lymphoid cells (ILC2) promoting acute skin inflammation. Filaggrin‐mutant (Flgft/ft) mice develop spontaneous skin inflammation accompanied by an increase in skin ILC2 numbers, IL‐1β production, and other cytokines recapitulating human AD. Here, we investigated the role of ILC2, effector cytokines, inflammasome activation, and mast cell function on the development of chronic AD‐like inflammation in mice.MethodsMice with a frameshift mutation in the filaggrin gene develop spontaneous dermatitis. Flgft/ft mice were crossed to cell‐ or cytokine‐deficient mouse strains, or bred under germ‐free conditions. Skin inflammation was scored, and microbiome composition was analyzed. Skin protein expression was measured by multiplex immunoassay. Infiltrating cells were analyzed by flow cytometry.ResultsWild‐type and Flgft/ft mice significantly differ in their microbiome composition. Furthermore, mutant mice do not develop skin inflammation under germ‐free conditions. ILC2 deficiency did not ameliorate chronic dermatitis in Flgft/ft mice, which was also independent of IL‐4, IL‐5, IL‐9, IL‐13, IL‐17A, and IL‐22. Inflammation was independent of NLRP3 inflammasome activation but required IL‐1β and IL‐1R1‐signaling. Mechanistically, IL‐1β promoted hyperactivation of IL‐1R1‐expressing mast cells. Treatment with anti‐IL‐1β‐antibody alleviated dermatitis exacerbation, while antibiotic intervention ameliorated dermatitis in neonatal mice but not in adults with established inflammation.ConclusionsIn summary, we identified a critical role for the microbiome and IL‐1β mediating chronic inflammation in mice with an impaired skin barrier.

Use of Stem Cells in Wound Healing

This review provides an overview of the principal stages of wound healing, the populations of endogenous and therapeutic stem cells, applications of stem cells in specific types of wounds, and current approaches of stem cell delivery for tissue regeneration. New uses of progenitor stem cells have been developed for the treatment of wounds. Stem cells improve wound healing through both local and paracrine effects. Stem cell populations of therapeutic utility include embryonic stem cells, induced pluripotent stem cells, adult bone marrow and adipose-derived mesenchymal stem cells, as well as stem cells from skin, cord blood, and extra fetal tissue. Induced pluripotent stem cells mitigate many of the ethical and immunogenic concerns related to use of embryonically derived stem cells. Skin, the largest organ in the human body, serves as a protective barrier for mammals. Both aging and disease contribute to loss of skin barrier function, which can result in consequences such as chronic wounds. Recent advances in many types of stem cell therapy may revolutionize treatment of difficult wounds. Optimal techniques for obtaining and delivering stem cells are still being refined.

Determinants of hand dermatitis, urticaria and loss of skin barrier function in professional cleaners in New Zealand.

This study assessed the risk of dermatitis, urticaria and loss of skin barrier function in 425 cleaners and 281 reference workers (retail workers and bus drivers). Symptoms, atopy and skin barrier function were assessed by questionnaire, skin prick tests, and measurement of transepidermal water loss. Cleaners had an increased risk of current (past 3months) hand/arm dermatitis (14.8% vs. 10.0%; OR=1.9, p<0.05) and urticaria (11% vs. 5.3%; OR=2.4, p<0.05) and were more likely to have dermatitis as adults (17.6% vs. 11.4%; OR=1.8, p<0.05). The risk of atopy was not increased, but associations with symptoms were more pronounced in atopics. Transepidermal water loss was significantly higher in cleaners. Wet-work was a significant risk factor for dermatitis and hand washing and drying significantly reduced the risk of urticaria. In conclusion, cleaners have an increased risk of hand/arm dermatitis, urticaria and loss of skin barrier function.

The lysosomal signaling anchor p18/LAMTOR1 controls epidermal development by regulating lysosome-mediated catabolic processes

The lysosomal adaptor protein p18 is an essential anchor of a scaffolding complex for the mTORC1 and MAPK pathways, which play crucial roles in controlling cell growth and energy homeostasis. To elucidate the in vivo function of the p18-mediated pathway, we conditionally ablated p18 in the mouse epidermis. Mutant mice were born with severe defects in formation of the stratum corneum and died within 12 h after birth due to dehydration caused by loss of skin barrier function. Mutant epidermal cells can grow and differentiate into granular cells, but exhibit functional defects in corneocyte maturation. Electron microscopy identified abnormal immature cells, overlying the mutant granular cells, which accumulated autophagosomes, glycogen granules and dead nuclei. Cell culture analysis showed that loss of p18 attenuated lysosome function, resulting in accumulation of immature lysosomes and autophagosomes. Analyses of lysosome behavior revealed that p18 is required for functional interaction between lysosomes and target organelles including autophagosomes. These findings suggest that p18-mediated pathways control lysosome-mediated catabolic processes, which are crucial for the development of mouse epidermis.

Inhibition of Transcription Factor Specificity Protein 1 Alters the Gene Expression Profile of Keratinocytes Leading to Upregulation of Kallikrein-Related Peptidases and Thymic Stromal Lymphopoietin

Transcription factor specificity protein 1 (Sp1) is involved in diverse cellular functions. We recently found that Sp1 was significantly decreased in skin biopsies from patients with atopic dermatitis (AD) and had an even greater reduction in AD patients with a history of eczema herpeticum. In the current study, we sought to better understand the role of Sp1 in skin biological processes by using a small interfering RNA (siRNA) technique to knock down Sp1 gene expression in normal human keratinocytes (NHK) and investigated the genome-wide gene expression profiling of Sp1- silenced NHK. The gene arrays revealed that 53 genes had more than three-fold changes in expression in Sp1-silenced NHK as compared to scrambled siRNA silenced cells. Strikingly, six kallikrein-related peptidase genes, KLK5, KLK6, KLK7, KLK8, KLK10, and KLK12 were up-regulated in NHK following Sp1 silencing. Functionally, protease activity was significantly enhanced in Sp1-silenced keratinocytes as compared to scrambled siRNA silenced keratinocytes. Moreover, thymic stromal lymphopoietin (TSLP), an epithelial derived TH2 promoting cytokine, was induced in Sp1-silenced keratinocytes due to elevated kallikrein activity. These results indicate that Sp1 expression deficiency leads to abnormally increased kallikrein protease activity in keratinocytes and may contribute to TH2 immune responses in the skin by inducing TSLP.

Could good eczema care prevent development of other atopic conditions?

The ‘atopic march’ describes the progression from eczema to other atopic conditions, mainly asthma and allergic rhinitis, and there has been a sharp rise in prevalence of all these conditions over the past few decades. Recent research suggests that changes in the skin barrier in early life are central to the development of atopy and there is gathering evidence to suggest that control or prevention of eczema in infancy may prevent future development of other atopic conditions. Genetic research has shed light on the susceptibility of some individuals to develop atopic conditions through defects in genes involved in skin barrier function. Several studies have demonstrated an increased risk of developing eczema in individuals with defects in the filaggrin gene, which is present in up to 10% of western European populations.1 Filaggrin is one of a number of structural proteins of the epidermis which contribute to maintaining an effective skin barrier. Mutations in the filaggrin gene result in loss of skin barrier function and the presence of atopic diseases, particularly eczema and asthma. Filaggrin gene defects are associated with an increased risk of developing asthma in individuals with eczema, but not those without eczema and, interestingly, filaggrin is not expressed in bronchial mucosa. Therefore, in individuals with filaggrin mutations, it seems that the breakdown in skin barrier plays a role in the development of asthma.2 It is hypothesised that lack of skin barrier function allows exposure to allergens through the skin and that the atopic march arises due to subsequent migration of sensitised T cells to the airways and nose. Mice models have shown that filaggrin mutations lead to increased uptake of …

IL-13Rα2 Has a Protective Role in a Mouse Model of Cutaneous Inflammation

IL-13 is expressed in lesions of atopic dermatitis (AD) and has been associated with increased disease severity. IL-13 has two cognate receptors: IL-13Rα1 and IL-13Rα2. Although IL-13Rα2 expression is known to be induced in response to IL-13 in keratinocytes, its function in AD has never been evaluated. We characterized the loss of skin barrier function and the development of cutaneous inflammation in IL-13Rα2-null versus wild-type BALB/c mice following an epicutaneous allergen-sensitization/challenge model that shares similarities with human AD. Mice lacking IL-13Rα2 had significantly increased transepidermal water loss, cutaneous inflammation, peripheral eosinophilia, and IgG1 and IgE levels compared with wild-type mice. The rate of resolution of the cutaneous inflammation was not significantly altered in the IL-13Rα2-null mice. IL-13 induced expression of IL-13Rα2 in keratinocyte cell lines and primary human keratinocytes. Depletion of IL-13Rα2 in a keratinocyte cell line resulted in increased STAT6 signaling in response to IL-13. In conclusion, IL-13Rα2 serves a protective role in the pathogenesis of allergic inflammation and loss of skin barrier function in a mouse model of AD, suggesting that it may be an important endogenous regulator of IL-13-induced cutaneous inflammation in humans.

Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity

Mutations in SPINK5, encoding the serine protease inhibitor LEKTI, cause Netherton syndrome, a severe autosomal recessive genodermatosis. Spink5(-/-) mice faithfully replicate key features of Netherton syndrome, including altered desquamation, impaired keratinization, hair malformation and a skin barrier defect. LEKTI deficiency causes abnormal desmosome cleavage in the upper granular layer through degradation of desmoglein 1 due to stratum corneum tryptic enzyme and stratum corneum chymotryptic enzyme-like hyperactivity. This leads to defective stratum corneum adhesion and resultant loss of skin barrier function. Profilaggrin processing is increased and implicates LEKTI in the cornification process. This work identifies LEKTI as a key regulator of epidermal protease activity and degradation of desmoglein 1 as the primary pathogenic event in Netherton syndrome.

Lethal, neonatal ichthyosis with increased proteolytic processing of filaggrin in a mouse model of Netherton syndrome

Netherton syndrome is an autosomal recessive multisystemic disorder characterized by congenital ichthyosiform erythroderma, hair shaft defects and atopy, caused by mutations within the human SPINK5 gene. To investigate the development of this disease, we have cloned mouse spink5 and created mice with a mutated premature stop codon at amino acid R820X, to produce an allele that closely mimics a point mutation (E827X) in human SPINK5. Newborn spink5(R820X/R820X) mice develop a lethal, severe ichthyosis with a loss of skin barrier function and dehydration, resulting in death within a few hours of birth, similar to that observed in patients with severe Netherton syndrome. Epidermal barrier function is compromised because of the stratum corneum becoming spontaneously detached in the newborn mice, and this is probably compounded by the reduced mechanical strength detected in the cornified envelopes. Biochemical analysis of skin from newborn wild-type and spink5(R820X/R820X) mice revealed a substantial increase in the proteolytic processing of profilaggrin into its constituent filaggrin monomers. Filaggrin functions to organize keratin filaments into highly ordered macrofibrils that crisscross the cornified cells of the stratum corneum imparting structural integrity, and defects in filaggrin processing occur in a number of forms of congenital ichthyosis. These data suggest that in the absence of the serine protease inhibitor spink5, there is an abnormal increase in the processing of profilaggrin, resulting in an overabundance of filaggrin monomers, and that this may play a direct role in the observed deficit in the adhesion of the stratum corneum and the severely compromised epidermal barrier function.

Klf4 is a transcription factor required for establishing the barrier function of the skin.

Located at the interface between body and environment, the epidermis must protect the body against toxic agents and dehydration, and protect itself against physical and mechanical stresses. Acquired just before birth and at the last stage of epidermal differentiation, the skin's proteinaceous/lipid barrier creates a surface seal essential for protecting animals against microbial infections and dehydration. We show here that Kruppel-like factor 4 (Klf4, encoded by the gene Klf4), highly expressed in the differentiating layers of epidermis, is both vital to and selective for barrier acquisition. Klf4-/- mice die shortly after birth due to loss of skin barrier function, as measured by penetration of external dyes and rapid loss of body fluids. The defect was not corrected by grafting of Klf4-/- skin onto nude mice. Loss of the barrier occurs without morphological and biochemical alterations to the well-known structural features of epidermis that are essential for mechanical integrity. Instead, late-stage differentiation structures are selectively perturbed, including the cornified envelope, a likely scaffold for lipid organization. Using suppressive subtractive hybridization, we identified three transcripts encoding cornified envelope proteins with altered expression in the absence of Klf4. Sprr2a is one, and is the only epidermal gene whose promoter is known to possess a functional Klf4 binding site. Our studies provide new insights into transcriptional governance of barrier function, and pave the way for unravelling the molecular events that orchestrate this essential process.

人の顔面皮膚における不全角化細胞の発生頻度と部位差

The purpose of this study was to investigate the incidence of parakeratotic stratum corneum cells on the cheek skin surface from 335 healthy subjects and the changes of them according to their ages. We also studied the quantitative levels of parakeratotic cells in various regions of face. Stratum corneum cells were collected by tape-stripping method and observed with hematoxyrin-eosin stain after formalin fixation.In our results, parakeratotic cells were observed in 68.4% of the total subjects, 64.4% of them were women and 72.7% of them were men. They were observed at about 80% in second and third decades of women and decreased as the age advanced. On the other hand, they were observed at about 80% after the first decade in men.Quantity of parakeratotic cells was the highest in upper cheek and followed by the forehead and nose. They were seldom observed below the cheek and chin.It was suggested that the parakeratotic cells were appeared in the stratum corneum cells in face, because our facial skin is always exposed to many external stimulations such as ultraviolet rays and so on and turn over of epidermis was accelerated. Moreover, we strongly suggested that sebum is one of the factor causing parakeratosis. Because parakeratotic cells were observed more frequently in the region where sebum level was high and most of them were observed around the pore of the hairs.Appearance of parakeratotic cells on skin surface implied the loss of skin barrier function and was important problem to the beauty and healthinèss of skin.