Barrier Defects Research Articles

Gut barrier defects, intestinal immune hyperactivation and enhanced lipid catabolism drive lethality in NGLY1-deficient Drosophila

Intestinal barrier dysfunction leads to inflammation and associated metabolic changes. However, the relative impact of gut bacteria versus non-bacterial insults on animal health in the context of barrier dysfunction is not well understood. Here, we establish that loss of Drosophila N-glycanase 1 (Pngl) in a specific intestinal cell type leads to gut barrier defects, causing starvation and JNK overactivation. These abnormalities, along with loss of Pngl in enterocytes and fat body, result in Foxo overactivation, leading to hyperactive innate immune response and lipid catabolism and thereby contributing to lethality. Germ-free rearing of Pngl mutants rescued their developmental delay but not lethality. However, raising Pngl mutants on isocaloric, fat-rich diets partially rescued lethality. Our data indicate that Pngl functions in Drosophila larvae to establish the gut barrier, and that the lethality caused by loss of Pngl is primarily mediated through non-bacterial induction of immune and metabolic abnormalities.

20 kDa isoform of connexin-43 augments spatial reorganization of the brain endothelial junctional complex and lesion leakage in cerebral cavernous malformation type-3

Cerebral cavernous malformation type-3 (CCM3) is a type of brain vascular malformation caused by mutations in programmed cell death protein-10 (PDCD10). It is characterized by early life occurrence of hemorrhagic stroke and profound blood-brain barrier defects. The pathogenic mechanisms responsible for microvascular hyperpermeability and lesion progression in CCM3 are still largely unknown. The current study examined brain endothelial barrier structural defects formed in the absence of CCM3 in vivo and in vitro that may lead to CCM3 lesion leakage. We found significant upregulation of a 20 kDa isoform of connexin 43 (GJA1–20 k) in brain endothelial cells (BEC) in both non-leaky and leaky lesions, as well as in an in vitro CCM3 knockdown model (CCM3KD-BEC). Morphological, biochemical, FRET, and FRAP analyses of CCM3KD-BEC found GJA1–20 k regulates full-length GJA1 biogenesis, prompting uncontrolled gap junction growth. Furthermore, by binding to a tight junction scaffolding protein, ZO-1, GJA1–20 k interferes with Cx43/ZO-1 interactions and gap junction/tight junction crosstalk, promoting ZO-1 dissociation from tight junction complexes and diminishing claudin-5/ZO-1 interaction. As a consequence, the tight junction complex is destabilized, allowing “replacement” of tight junctions with gap junctions leading to increased brain endothelial barrier permeability. Modifying cellular levels of GJA1–20 k rescued brain endothelial barrier integrity re-establishing the spatial organization of gap and tight junctional complexes. This study highlights generation of potential defects at the CCM3-affected brain endothelial barrier which may underlie prolonged vascular leakiness.

Atopic dermatitis and the human skin microbiota

The skin microbiota is a complex ecosystem consisting of bacteria, fungi and viruses. The role of the human skin microbiota is to maintain homeostasis in the body. Disruption of the balance of the natural composition of the human microbiome can lead to the development of inflammation and infection. Atopic dermatitis is a chronic and recurrent non-infectious, inflammatory dermatosis characterised by erythematous and exfoliative skin lesions, accompanied by pruritus and a tendency to superinfection. Defect in the epidermal barrier, immune dysfunction and changes in the composition of the skin microbiome underlie the pathogenesis of atopic dermatitis. It has been found that the diversity of atopic skin microbiota is significantly reduced, with a decrease in the number of Cutibacterium, Streptococcus, Acinetobacter, Corynebacterium and Prevotella, and a concomitant increase in the percentage of Staphylococcus bacteria, especially S. aureus. It accounts for about 20% of skin microbiome in healthy people, while in patients with atopic dermatitis the percentage of S. aureus can increase up to 30–100%. In addition, there is a positive correlation between S. aureus skin colonisation and disease severity. S. aureus plays a key role in the development of skin inflammation in the course of atopic dermatitis, including through the induction of lymphocyte expansion, release of cytokines, pro-inflammatory lipoproteins, and stimulation of mast cell degranulation. Therefore, properly selected and regular treatment of atopic dermatitis diversifies the skin microflora, often leading to clinical improvement in the patient.

The immunological and structural epidermal barrier dysfunction and skin microbiome in atopic dermatitis-an update.

Atopic dermatitis (AD) is a common, chronic and relapsing inflammatory skin disease with various clinical presentations and combinations of symptoms. The pathophysiology of AD is complex and multifactorial. There are several factors involved in the etiopathogenesis of AD including structural and immunological epidermal barrier defect, imbalance of the skin microbiome, genetic background and environmental factors. Alterations in structural proteins, lipids, proteases, and their inhibitors, lead to the impairment of the stratum corneum which is associated with the increased skin penetration and transepidermal water loss. The elevated serum immunoglobulin E levels and blood eosinophilia have been shown in the majority of AD patients. Type 2 T-helper cell immune pathway with increased expression of interleukin (IL)-4, IL-5, and IL-13, has an important role in the etiopathogenesis of AD. Both T cells and keratinocytes contribute to epidermal barrier impairment in AD via a dynamic interaction of cytokines and chemokines. The skin microbiome is another factor of relevance in the etiopathogenesis of AD. It has been shown that during AD flares, Staphylococcus aureus (S. aureus) colonization increased, while Staphylococcus epidermidis (S. epidermidis) decreased. On the contrary, S. epidermidis and species of Streptococcus, Corynebacterium and Propionibacterium increased during the remision phases. However, it is not clear whether skin dysbiosis is one of the symptoms or one of the causes of AD. There are several therapeutic options, targeting these pathways which play a critical role in the etiopathogenesis of AD. Although topical steroids are the mainstay of the treatment of AD, new biological therapies including IL-4, IL-13, and IL-31 inhibitors, as well as Janus kinase inhibitors (JAKi), increasingly gain more importance with new advances in the therapy of AD. In this review, we summarize the role of immunological and structural epidermal barrier dysfunction, immune abnormalities, impairment of lipids, filaggrin mutation and skin microbiome in the etiopathogenesis of AD, as well as the therapeutic options for AD and their effects on these abnormalities in AD skin.

Coffea arabica Extract Attenuates Atopic Dermatitis-like Skin Lesions by Regulating NLRP3 Inflammasome Expression and Skin Barrier Functions.

Atopic dermatitis (AD) is a common skin disease worldwide. The major causes of AD are skin barrier defects, immune dysfunction, and oxidative stress. In this study, we investigated the anti-oxidation and anti-inflammation effects of Coffea arabica extract (CAE) and its regulation of the skin barrier and immune functions in AD. In vitro experiments revealed that CAE decreased the reactive oxygen species levels and inhibited the translocation of nuclear factor-κB (NF-κB), further reducing the secretion of interleukin (IL)-1β and IL-6 induced by interferon-γ (IFN-γ)/tumor necrosis factor-α (TNF-α). Moreover, CAE decreased IFN-γ/TNF-α-induced NLR family pyrin domain-containing 3 (NLRP3), caspase-1, high-mobility group box 1 (HMGB1), and receptor for advanced glycation end products (RAGE) expression levels. It also restored the protein levels of skin barrier function-related markers including filaggrin and claudin-1. In vivo experiments revealed that CAE not only reduced the redness of the backs of mice caused by 2,4-dinitrochlorobenzene (DNCB) but also reduced the levels of pro-inflammatory factors in their skin. CAE also reduced transepidermal water loss (TEWL) and immune cell infiltration in DNCB-treated mice. Overall, CAE exerted anti-oxidation and anti-inflammation effects and ameliorated skin barrier dysfunction, suggesting its potential as an active ingredient for AD treatment.

Personalized Response of Parkinson's Disease Gut Microbiota to Nootropic Medicinal Herbs In Vitro: A Proof of Concept.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons. Although the etiology of PD remains elusive, it has been hypothesized that initial dysregulation may occur in the gastrointestinal tract and may be accompanied by gut barrier defects. A strong clinical interest in developing therapeutics exists, including for the treatment of gut microbiota and physiology. We previously reported the impact of healthy fecal microbiota anaerobic cultures supplemented with nootropic herbs. Here, we evaluated the effect of nootropic Ayurvedic herbs on fecal microbiota derived from subjects with PD in vitro using 16S rRNA sequencing. The microbiota underwent substantial change in response to each treatment, comparable in magnitude to that observed from healthy subjects. However, the fecal samples derived from each participant displayed unique changes, consistent with a personalized response. We used genome-wide metabolic reconstruction to predict the community's metabolic potential to produce products relevant to PD pathology, including SCFAs, vitamins and amino acid degradation products. These results suggest the potential value of conducting in vitro cultivation and analyses of PD stool samples as a means of prescreening patients to select the medicinal herbs for which that individual is most likely to respond and derive benefit.

Type 2 chronic inflammatory diseases: targets, therapies and unmet needs.

Over the past twodecades, significant progress in understanding of the pathogenesis of type 2 chronic inflammatory diseases has enabled the identification of compounds for more than 20 novel targets, which are approved or at various stages of development, finally facilitating a more targeted approach for the treatment of these disorders. Most of these newly identified pathogenic drivers of type 2 inflammation and their corresponding treatments are related to mast cells, eosinophils, T cells, B cells, epithelial cells and sensory nerves. Epithelial barrier defects and dysbiotic microbiomes represent exciting future drug targets for chronic type 2 inflammatory conditions. Here, we review common targets, current treatments and emerging therapies for the treatment of five major type 2 chronic inflammatory diseases - atopic dermatitis, chronic prurigo, chronic urticaria, asthma and chronic rhinosinusitis with nasal polyps - with a high need for targeted therapies. Unmet needs and future directions in the field are discussed.

Systemic cytokines inhibition with Imp7 siRNA nanoparticle ameliorates gut injury in a mouse model of ventilator-induced lung injury

Mechanical ventilation (MV) may negatively affect the lungs and cause the release of inflammatory mediators, resulting in extra-pulmonary organ dysfunction. Studies have revealed systemically elevated levels of proinflammatory cytokines in animal models of ventilator-induced lung injury (VILI); however, whether these cytokines have an effect on gut injury and the mechanisms involved remain unknown. In this study, VILI was generated in mice with high tidal volume mechanical ventilation (20 ml/kg). Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 concentrations in serum and gut measured by ELISA showed significant elevation in the VILI mice. Significant increases in gut injury and PANoptosis were observed in the VILI mice, which were positively correlated with the serum levels of TNF-α, IL-1β, and IL-6. The VILI mice displayed intestinal barrier defects, decreased expressions of occludin and zonula occludin-1 (ZO-1), and increased expression of claudin-2 and the activation of myosin light chain (MLC). Importantly, intratracheal administration of Imp7 siRNA nanoparticle effectively inhibited cytokines production and protected mice from VILI-induced gut injury. These data provide evidence of systemic cytokines contributing to gut injury following VILI and highlight the possibility of targeting cytokines inhibition via Imp7 siRNA nanoparticle as a potential therapeutic intervention for alleviating gut injury following VILI.

Allergic Diseases and Childhood Obesity: A Detrimental Link?

Several epidemiological studies have described childhood obesity as a risk factor for atopic disease, particularly asthma. At the same time, this association seems to be more conflicting for allergic rhinitis, atopic dermatitis, and chronic urticaria. This article aims to deepen the possibility of a relationship between childhood obesity and allergic diseases. As regards asthma, the mechanical and inflammatory effects of obesity can lead to its development. In addition, excess adiposity is associated with increased production of inflammatory cytokines and adipokines, leading to low-grade systemic inflammation and an increased risk of asthma exacerbations. Allergic rhinitis, atopic dermatitis, food allergies, and chronic urticaria also seem to be related to this state of chronic low-grade systemic inflammation typical of obese children. Vitamin D deficiency appears to play a role in allergic rhinitis, while dyslipidemia and skin barrier defects could explain the link between obesity and atopic dermatitis. Starting from this evidence, it becomes of fundamental importance to act on body weight control to achieve general and allergic health, disentangling the detrimental link between obesity allergic diseases and childhood obesity. Further studies on the association between adiposity and atopy are needed, confirming the biologically active role of fat tissue in the development of allergic diseases and exploring the possibility of new therapeutic strategies.

MOF-mediated histone H4 Lysine 16 acetylation governs mitochondrial and ciliary functions by controlling gene promoters

Histone H4 lysine 16 acetylation (H4K16ac), governed by the histone acetyltransferase MOF, orchestrates gene expression regulation and chromatin interaction. However, the roles of MOF and H4K16ac in controlling cellular function and regulating mammalian tissue development remain unclear. Here we show that conditional deletion of Mof in the skin, but not Kansl1, causes severe defects in the self-renewal of basal epithelial progenitors, epidermal differentiation, and hair follicle growth, resulting in barrier defects and perinatal lethality. MOF-regulated genes are highly enriched for essential functions in the mitochondria and cilia. Genetic deletion of Uqcrq, an essential subunit for the electron transport chain (ETC) Complex III, in the skin, recapitulates the defects in epidermal differentiation and hair follicle growth observed in MOF knockout mouse. Together, this study reveals the requirement of MOF-mediated epigenetic mechanism for regulating mitochondrial and ciliary gene expression and underscores the important function of the MOF/ETC axis for mammalian skin development.

Exosome from IFN-γ-Primed Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Improved Skin Inflammation and Barrier Function.

The pathogenesis of atopic dermatitis (AD) is multifactorial, including immune dysregulation and epidermal barrier defects, and a novel therapeutic modality that can simultaneously target multiple pathways is needed. We investigated the therapeutic effects of exosomes (IFN-γ-iExo) secreted from IFN-γ-primed induced pluripotent stem cell-derived mesenchymal stem cells (iMSC) in mice with Aspergillus fumigatus-induced AD. IFN-γ-iExo was epicutaneously administered to mice with AD-like skin lesions. The effects of IFN-γ-iExo treatment were investigated through clinical scores, transepidermal water loss (TEWL) measurements, and histopathology. To elucidate the therapeutic mechanism, we used an in vitro model of human keratinocyte HaCaT cells stimulated with IL-4 and IL-13 and performed extensive bioinformatics analysis of skin mRNA from mice. The expression of indoleamine 2,3-dioxygenase was higher in IFN-γ primed iMSCs than in iMSCs. In human keratinocyte HaCaT cells, treatment with IFN-γ-iExo led to decreases in the mRNA expression of thymic stromal lymphopoietin, IL-25, and IL-33 and increases in keratin 1, keratin 10, desmoglein 1, and ceramide synthase 3. IFN-γ-iExo treatment significantly improved clinical and histological outcomes in AD mice, including clinical scores, TEWL, inflammatory cell infiltration, and epidermal thickness. Bioinformatics analysis of skin mRNA from AD mice showed that IFN-γ-iExo treatment is predominantly involved in skin barrier function and T cell immune response. Treatment with IFN-γ-iExo improved the clinical and histological outcomes of AD mice, which were likely mediated by restoring proper skin barrier function and suppressing T cell-mediated immune response.

Efficacy of Chitosan Scaffolded Calcium Silicate-based Cements for Treating Internal Resorption Defects with Perforation: In Vitro Study.

The present study aimed to evaluate the efficacy of chitosan scaffold combined with calcium silicate cements in the management of internal resorption with perforation. Internal resorption cavities were simulated in 20 human permanent maxillary incisors that were then divided into two groups: group I - biodentine and group II - chitosan scaffold combined with biodentine. The samples were evaluated for the mineralization activity at the end of the 7th day and 14th day using scanning electron microscopy-energy dispersive X-ray (SEM-EDX) analysis. The data were recorded, tabulated, and then statistically analyzed. From the SEM-EDX analysis, the mean score of calcium and phosphorus ion uptake by the material was obtained. Statistical analysis by nonparametric Mann-Whitney test showed that there was statistically significant difference in calcium ion uptake at the end of the 7th day (p = 0.016) and at the end of 14th day (p = 0.043) between the group biodentine and group chitosan scaffold combined with biodentine (p < 0.05). In this present study, the use of chitosan scaffolds combined with biodentine showed a statistically significant difference in the mineralization activity when compared with pure biodentine. These scaffolded biomaterials exhibited greater potential for mineralization in vitro which can be efficiently used for the management of teeth with internal resorption with perforation. Further clinical trials are required for the understanding of their behavior in real-world scenarios. Calcium silicate cements have often exhibited defective hard tissue barrier formation and hence there is a pressing need to search for newer biomaterials that can overcome these shortcomings. Scaffolded biomaterials provide a controlled microcellular environment for bioactivity, and they were found to be efficient in the remineralization of tooth structure. The present study findings indicate that these chitosan scaffolds can be efficiently used in combination with calcium silicate cements for the management of internal resorption with perforation to enhance the treatment outcome.

O13 JAK inhibitors to restore skin barrier function in ARCI

Abstract The autosomal recessive congenital ichthyoses (ARCI) are a group of chronic conditions where there is unmet therapeutic need. Harlequin ichthyosis (HI) is the most severe form of ARCI, with aberrant differentiation of the epidermis leading to a severe barrier defect. It is caused by mutations in ABCA12, a lipid transporter involved in the transport of glucosylceramides from the lamellar body to the lipid lamellae. Lamellar ichthyosis is caused by mutations in TGM1. Several Janus kinase (JAK) inhibitors (JAKi) inhibiting the JAK–STAT pathway are now licensed for atopic dermatitis. Previous work from our group in an in vitro HI model showed that tofacitinib had a restorative effect on the lipid barrier. We hypothesized that JAKi A, B and C could restore the epidermal barrier in both HI three-dimensional (3D) organotypic models (OTs) made using ABCA12 CrispR-Cas9 knockout and wild-type keratinocytes and ARCI 3D OTs generated with short hairpin RNA knock down of TGM1. The JAKi were tested at three concentrations in the 3D models (20, 50 and 500 nmol L–1 for JAKiA; 10, 50 and 250 nmol L–1 for JAKiB; 2, 25 and 125 nmol L–1 for JAKiC) and vehicle only was used as the control. The OTs were stained with haematoxylin and eosin, Nile red and differentiation markers such as K10, K14, transglutaminase 1 (TGM1) and involucrin. All three JAKi had a positive effect on the epidermal barrier. The epidermal structure looked more organized and uniform, with an increase in neutral and polar lipids in the upper epidermis. The differentiation markers showed normalization of the expression of involucrin, K10 and TGM1 at the same drug concentrations. These results suggest that JAKi have a generalized positive effect on the skin barrier and will be further investigated in an in vivo mouse model of HI.

P26 Characterization of skin barrier defects in atopic dermatitis patients using attenuated total reflection Fourier transform infrared spectroscopy

P26 Characterization of skin barrier defects in atopic dermatitis patients using attenuated total reflection Fourier transform infrared spectroscopy

The epidermal lipid barrier in microbiome-skin interaction.

The corneocyte layers forming the upper surface of mammalian skin are embedded in a lamellar-membrane matrix which repels harmful molecules while retaining solutes from subcutaneous tissues. Only certain bacterial and fungal taxa colonize skin surfaces. They have ways to use epidermal lipids as nutrients while resisting antimicrobial fatty acids. Skin microorganisms release lipophilic microbe-associated molecular pattern (MAMP) molecules which are largely retained by the epidermal lipid barrier. Skin barrier defects, as in atopic dermatitis, impair lamellar-membrane integrity, resulting in altered skin microbiomes, which then include the pathogen Staphylococcus aureus. The resulting increased penetration of MAMPs and toxins promotes skin inflammation. Elucidating how microorganisms manipulate the epidermal lipid barrier will be key for better ways of preventing inflammatory skin disorders.

Biodegradable Packaging Materials for Foods Preservation: Sources, Advantages, Limitations, and Future Perspectives

Biodegradable packaging materials generally comprise a solution to the environmental problem caused by the consecutive use of conventional packaging materials (petroleum-based materials) even though these have a high cost. The monomers resulting from the slow degradation of petroleum-based materials contribute to the pollution of the environment. Biodegradable packaging materials distinguished by high biodegradability and biocompatibility can successfully replace the aforementioned packaging materials and thus solve the environmental problems caused by their use or deposition. Although several of the biodegradable packaging materials present defective properties, mainly mechanical and barrier properties, these are reduced or even eliminated by the addition of various improving additives and by blending them with other biopolymers. Various natural preservatives such as essential oils or other phytochemical extracts can also be incorporated into the biopolymer network to increase its efficacy. This treatment is particularly beneficial since it contributes to the increasing of the shelf life and storability of packaged foods such as fruits, vegetables, dairy products, meat and its products, poultry, and fish. For all the above reasons, the preferences of consumers and the critical thinking/decisions of the food product manufacturing industries in favor of the potential use of biodegradable packaging materials in foods are increasing more and more. In this context, the present review article addresses the most recently used biodegradable packaging materials for foods preservation by presenting their sources, advantages, limitations, and future perspectives.

Myeloid Cell-Specific Deletion of PDGFR-α Promotes Dysbiotic Intestinal Microbiota and thus Increased Colitis Susceptibility.

The incidence of inflammatory bowel diseases [IBD] is steadily increasing, and thus the identification of new targets to improve therapy is a major goal. Growth factors of the PDGF family and their receptors are expressed early in intestinal development and are found in mononuclear cells and macrophages in adult tissues. Macrophages play a distinct role in the pathogenesis of IBD since their function is crucial to maintaining tolerance. We aimed to study the role of myeloid expression of PDGFR-α in mediating intestinal homeostasis in mouse IBD and infectious models. Our results show that loss of myeloid PDGFR-α increases susceptibility to dextran saline sulphate-induced colitis. Accordingly, LysM-PDGFR-α-/- mice showed higher colitis scores, and reduced levels of anti-inflammatory macrophages compared to control mice. This effect was mediated via a pro-colitogenic microbiota, which developed in the absence of myeloid PDGFR-α and caused increased colitis susceptibility in gnotobiotic mice upon faecal microbiota transplantation compared to controls. Furthermore, LysM-PDGFR-α-/- mice had a leaky gut, accompanied by impaired phagocytosis, resulting in a severe barrier defect. Taken together, our results indicate a protective role for myeloid PDGFR-α in maintaining gut homeostasis by promoting a protective intestinal microbiota and providing an anti-inflammatory macrophage phenotype.

Particulate matter 10 exposure affects intestinal functionality in both inflamed 2D intestinal epithelial cell and 3D intestinal organoid models.

A growing body of evidence suggests that particulate matter (PM10) enters the gastrointestinal (GI) tract directly, causing the GI epithelial cells to function less efficiently, leading to inflammation and an imbalance in the gut microbiome. PM10 may, however, act as an exacerbation factor in patients with inflamed intestinal epithelium, which is associated with inflammatory bowel disease. The purpose of this study was to dissect the pathology mechanism of PM10 exposure in inflamed intestines. In this study, we established chronically inflamed intestinal epithelium models utilizing two-dimensional (2D) human intestinal epithelial cells (hIECs) and 3D human intestinal organoids (hIOs), which mimic in vivo cellular diversity and function, in order to examine the deleterious effects of PM10 in human intestine-like in vitro models. Inflamed 2D hIECs and 3D hIOs exhibited pathological features, such as inflammation, decreased intestinal markers, and defective epithelial barrier function. In addition, we found that PM10 exposure induced a more severe disturbance of peptide uptake in inflamed 2D hIECs and 3D hIOs than in control cells. This was due to the fact that it interferes with calcium signaling, protein digestion, and absorption pathways. The findings demonstrate that PM10-induced epithelial alterations contribute to the exacerbation of inflammatory disorders caused by the intestine. According to our findings, 2D hIEC and 3D hIO models could be powerful in vitro platforms for the evaluation of the causal relationship between PM exposure and abnormal human intestinal functions.

Genomic, Epigenomic, Transcriptomic, Proteomic and Metabolomic Approaches in Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with a high prevalence in the developed countries. It is associated with atopic and non-atopic diseases, and its close correlation with atopic comorbidities has been genetically demonstrated. One of the main roles of genetic studies is to comprehend the defects of the cutaneous barrier due to filaggrin deficit and epidermal spongiosis. Recently, epigenetic studies started to analyze the influence of the environmental factors on gene expression. The epigenome is considered to be a superior second code that controls the genome, which includes alterations of the chromatin. The epigenetic changes do not alter the genetic code, however, changes in the chromatin structure could activate or inhibit the transcription process of certain genes and consequently, the translation process of the new mRNA into a polypeptide chain. In-depth analysis of the transcriptomic, metabolomic and proteomic studies allow to unravel detailed mechanisms that cause AD. The extracellular space and lipid metabolism are associated with AD that is independent of the filaggrin expression. On the other hand, around 45 proteins are considered as the principal components in the atopic skin. Moreover, genetic studies based on the disrupted cutaneous barrier can lead to the development of new treatments targeting the cutaneous barrier or cutaneous inflammation. Unfortunately, at present, there are no target therapies that focus on the epigenetic process of AD. However, in the future, miR-143 could be an important objective for new therapies, as it targets the miR-335:SOX axis, thereby restoring the miR-335 expression, and repairing the cutaneous barrier defects.

Loricrin and Cytokeratin Disorganisation in Severe Forms of Periodontitis

ObjectiveThe aim of this research was to investigate the role of the cornified epithelium, the outermost layer of the oral mucosa, engineered to prevent water loss and microorganism invasion, in severe forms of periodontitis (stage III or IV, grade C). MethodsPorphyromonas gingivalis, a major periodontal disease pathogen, can affect cornified epithelial protein expression through chronic activation of signal transducer and activator of transcription 6 (Stat6). We used a mouse model, Stat6VT, that mimics this to determine the effects of barrier defect on P gingivalis–induced inflammation, bone loss, and cornified epithelial protein expression, and compared histologic and immunohistologic findings with tissues obtained from human controls and patients with stage III and IV, grade C disease. Alveolar bone loss in mice was assessed using micro-computerised tomography, and soft tissue morphology was qualitatively and semi-quantitatively assessed by histologic examination for several proteins, including loricrin, filaggrin, cytokeratin 1, cytokeratin 14, a proliferation marker, a pan-leukocyte marker, as well as morphologic signs of inflammation. Relative cytokine levels were measured in mouse plasma by cytokine array. ResultsIn the tissues from patients with periodontal disease, there were greater signs of inflammation (rete pegs, clear cells, inflammatory infiltrates) and a decrease and broadening of expression of loricrin and cytokeratin 1. Cytokeratin 14 expression was also broader and decreased in stage IV. P gingivalis–infected Stat6VT mice showed greater alveolar bone loss in 9 out of 16 examined sites, and similar patterns of disruption to human patients in expression of loricrin and cytokeratins 1 and 14. There were also increased numbers of leukocytes, decreased proliferation, and greater signs of inflammation compared with P gingivalis–infected control mice. ConclusionsOur study provides evidence that changes in epithelial organisation can exacerbate the effects of P gingivalis infection, with similarities to the most severe forms of human periodontitis.