ABSTRACT
BACKGROUND: Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease. Although murine studies have demonstrated that type 2 innate lymphoid cells (ILCs) mediate type 2 skin inflammation, their role in skin fibrosis in AD remains unclear. This study investigated whether type 2 ILCs are involved in skin fibrosis using an AD-like murine model. METHODS: C57BL/6 mice were treated epicutaneously with Aspergillus fumigatus (Af) for 5 consecutive days per week for 5 weeks to induce skin fibrosis. Mature lymphocyte deficient Rag1-/- mice were also used to investigate the role of type 2 ILCs in skin fibrosis. RESULTS: The clinical score and transepidermal water loss (TEWL) were significantly higher in the AD group than in the control group. The AD group also showed significantly increased epidermal and dermal thicknesses and significantly higher numbers of eosinophils, neutrophils, mast cells, and lymphocytes in the lesional skin than the control group. The lesional skin of the AD group showed increased stain of collagen and significantly higher levels of collagen than the control group (10.4 ± 2.2 µg/mg vs. 1.6 ± 0.1 µg/mg, P < 0.05). The AD group showed significantly higher populations of type 2 ILCs in the lesional skin compared to the control group (0.08 ± 0.01% vs. 0.03 ± 0.01%, P < 0.05). These findings were also similar with the AD group of Rag1-/- mice compared to their control group. Depletion of type 2 ILCs with anti-CD90.2 monoclonal antibodies significantly improved clinical symptom score, TEWL, and infiltration of inflammatory cells, and significantly decreased levels of collagen were observed in the AD group of Rag1-/- mice (1.6 ± 0.0 µg/mg vs. 4.5 ± 0.3 µg/mg, P < 0.001). CONCLUSION: In the Af-induced AD-like murine model, type 2 ILCs were elevated, with increased levels of collagen. Additionally, removal of type 2 ILCs resulted in decreased collagen levels and improved AD-like pathological findings. These findings suggest that type 2 ILCs play a role in the mechanism of skin fibrosis in AD.
Subject(s)
Dermatitis, Atopic , Disease Models, Animal , Fibrosis , Homeodomain Proteins , Immunity, Innate , Lymphocytes , Mice, Inbred C57BL , Skin , Animals , Dermatitis, Atopic/pathology , Dermatitis, Atopic/immunology , Lymphocytes/immunology , Mice , Skin/pathology , Skin/immunology , Homeodomain Proteins/metabolism , Homeodomain Proteins/genetics , Aspergillus fumigatus/immunology , Collagen/metabolism , Mice, Knockout , Mast Cells/immunology , Eosinophils/pathology , Eosinophils/immunology , FemaleABSTRACT
Conventional histopathological features of psoriasis and atopic dermatitis often overlap. We aimed to investigate Galectin-3 (Gal-3) expression in psoriatic skin lesions and its potential as an immunohistochemical marker for distinguishing between psoriasis and atopic dermatitis on a pathological basis. Based on immunohistochemical analysis, we assessed Gal-3 expression in formalin-fixed, paraffin-embedded tissue sections from 21 patients with psoriasis and 15 patients with atopic dermatitis. Quantitative analysis of expression intensity was performed using the average density (average optical density) method. We analysed the relationship between Gal-3 expression and clinical characteristics, as well as conventional histopathological features. Patients with psoriasis exhibited significantly decreased Gal-3 expression in the epidermis (0.11±0.05) compared to the atopic dermatitis group (0.36±0.15) and healthy controls (0.49±0.13) (p<0.0001). Reduction in Gal-3 expression in the psoriatic epidermis around areas of neutrophil aggregation was more pronounced than around areas of non-neutrophil aggregation (0.07±0.02 vs 0.16±0.05, p<0.01). In both psoriasis (r=-0.48, p<0.05) and atopic dermatitis groups (r=-0.70, p<0.01), Gal-3 expression negatively correlated with epidermal thickness. When epidermal thickness was matched between the two groups, the decrease in epidermal Gal-3 expression remained significant in the psoriasis group compared to the atopic dermatitis group (0.14±0.05 Vs 0.30±0.07, p<0.01). Patients with psoriasis show specific downregulation of epidermal Gal-3, correlating with epidermal thickness and neutrophil-related factors. Gal-3 may serve as an auxiliary discriminative marker between psoriasis and atopic dermatitis, potentially associated with keratinocyte proliferation and neutrophil function.
Subject(s)
Dermatitis, Atopic , Epidermis , Galectin 3 , Psoriasis , Humans , Psoriasis/metabolism , Psoriasis/pathology , Epidermis/metabolism , Epidermis/pathology , Galectin 3/metabolism , Galectin 3/analysis , Female , Male , Dermatitis, Atopic/metabolism , Dermatitis, Atopic/pathology , Adult , Middle Aged , Biomarkers/metabolism , Biomarkers/analysis , Immunohistochemistry , Case-Control Studies , Young Adult , Aged , Diagnosis, DifferentialABSTRACT
Atopic dermatitis (AD) is a prevalent and chronic inflammatory skin condition characterized by a multifaceted pathophysiology that gives rise to diverse clinical manifestations. The management of AD remains challenging due to the suboptimal efficacy of existing treatment options. Nonetheless, recent progress in elucidating the underlying mechanisms of the disease has facilitated the identification of new potential therapeutic targets and promising drug candidates. In this review, we summarize the newest data, considering multiple connections between IL-22 and AD. The presence of circulating IL-22 has been found to correlate with the severity of AD and is identified as a critical factor driving the inflammatory response associated with the condition. Elevated levels of IL-22 in patients with AD are correlated with increased proliferation of keratinocytes, alterations in the skin microbiota, and impaired epidermal barrier function. Collectively, these factors contribute to the manifestation of the characteristic symptoms observed in AD.
Subject(s)
Dermatitis, Atopic , Interleukin-22 , Interleukins , Dermatitis, Atopic/pathology , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/immunology , Humans , Interleukins/metabolism , Animals , Keratinocytes/metabolism , Skin/pathology , Skin/metabolism , MicrobiotaABSTRACT
We previously reported that a pathogenic abnormality in the barrier and water-holding functions of the stratum corneum (SC) in the skin of patients with atopic dermatitis (AD) is mainly attributable to significantly decreased levels of total ceramides in the SC. That decrease is mediated by the abnormal expression of a novel ceramide-reducing enzyme, sphingomyelin/glucosylceramide deacylase (SGDase), which is the ß-subunit (ASAH1b) of acid ceramidase. In this study, we determined whether mice overexpressing ASAH1b in their epidermis develop AD-like skin symptoms. We generated transgenic (TG) mice overexpressing ASAH1b, regulated by the involucrin promoter, to localize its expression in the upper epidermis. After hair removal using a depilatory cream containing glycolic acid, the TG mice without any visible skin inflammation at 8 weeks of age had increased levels of ASAH1b and decreased levels of SC ceramide, with disrupted barrier functions measured by trans-epidermal water loss compared to the wild-type (WT) mice. Interestingly, enzymatic assays revealed that SGDase activity was not detectable in the skin of the TG mice compared to WT mice. Immunological staining revealed that there was an increased expression level of IL-33 in the epidermis and an accumulation of macrophages in the dermis of TG mice compared to WT mice, which are phenotypic characteristics of AD, that were exacerbated by tape-stripping of the skin. In the skin of the TG mice, the mRNA levels of IL-5, CCL11, IL-22, CXCL10, and IFNγ were significantly upregulated compared to the WT mice, and tape-stripping significantly increased the mRNA levels of IL-4, IL-33, CXCL1, CXCL12, TLR9, and CD163 compared to WT mice. These findings strongly indicate that the skin of the depilatory cream-treated TG mice exists in an atopic dry skin condition that is highly sensitive to various environmental stimuli. The sum of our results suggests that ASAH1b itself, even in the absence of its enzymatic activity, is a major etiologic factor for atopic dry skin symptoms via an unknown mechanism.
Subject(s)
Acid Ceramidase , Ceramides , Dermatitis, Atopic , Epidermis , Mice, Transgenic , Animals , Dermatitis, Atopic/metabolism , Dermatitis, Atopic/genetics , Dermatitis, Atopic/pathology , Epidermis/metabolism , Epidermis/pathology , Acid Ceramidase/metabolism , Acid Ceramidase/genetics , Mice , Ceramides/metabolism , Disease Models, Animal , Skin/metabolism , Skin/pathologyABSTRACT
BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory cutaneous disorder, that emerges from intricate interplays among genetic predisposition, immune dysregulation, environmental factors, and compromised skin barrier. Understanding the inflammatory pathway in AD is important due to its fundamental role in the pathogenesis of AD. This study aimed to explore the diverse spectrum of proteins linked to the inflammation of AD and the relationship between systemic biomarkers and clinical severity in AD. METHODS: We examined the blood samples from 48 patients with AD and 48 healthy controls (HCs) using the Proximity Extension Assay (Olink). Differentially expressed proteins (DEPs) were identified and Pearson correlation analysis was conducted to determine systemic proteomic biomarkers associated with severity of AD. RESULTS: A total of 29 DEPs were significantly up-regulated and 2 DEPs were significantly down-regulated in AD compared with the HC. The MCP-4, IL-18, MCP-3, TNFRSF9, and IL-17C were the top 5 highest DEPs associated with the severity of AD. CONCLUSION: Our study sheds light on the intricate network of inflammatory proteins in AD and their potential implications for disease severity. Our results indicate that these systemic inflammatory proteins could be valuable for assessing AD severity and enhancing our understanding of the disease's complexity and its potential management strategies.
Subject(s)
Biomarkers , Dermatitis, Atopic , Proteomics , Severity of Illness Index , Humans , Dermatitis, Atopic/blood , Dermatitis, Atopic/pathology , Dermatitis, Atopic/diagnosis , Biomarkers/blood , Biomarkers/metabolism , Female , Male , Adult , Case-Control Studies , Young Adult , Inflammation/metabolism , Adolescent , Middle AgedABSTRACT
OBJECTIVE: Atopic dermatitis (AD) is characterized by compositional and structural changes to the skin at lesional sites. Alteration to the levels and organization of both protein and lipid components are associated with disease status and lead to impaired barrier and hydration. Corneodesmosin (CDSN) and the arrangement and length of the intercellular lipid lamellae (ICLL) are altered in disrupted skin states. The aim of this research was to profile the distribution of CDSN and the ICLL in the stratum corneum (SC) at lesional and non-lesional sites in AD-prone skin and to investigate the impact of an eczema calming lotion containing petroleum jelly, fatty acids, and colloidal oatmeal. METHODS: An IRB-approved study was conducted with participants with active AD. From a small subset of participants, tape strips were collected from lesional and non-lesional sites on the arm, prior to and after twice daily application, over 4 weeks of an eczema calming lotion containing petroleum jelly, fatty acids, and colloidal oatmeal. Fluorescent antibody staining was used to investigate the distribution of CDSN. Transmission electron microscopy (TEM) was used to characterize the ICLL. RESULTS: The distribution/coverage of CDSN was similar between lesional and non-lesional sites at baseline; application of the lotion resulted in a more defined honeycomb/peripheral distribution. Normalized ICLL (nICLL) was lower in baseline samples from lesional sites relative to non-lesional sites. Application of the lotion increased this parameter by the end of the study at all sites. CONCLUSION: The eczema calming lotion containing petroleum jelly, fatty acids and colloidal oatmeal provided changes in corneodesmosomal proteins distribution and ICLL, consistent with improvements in corneocyte maturation and improved barrier function in the skin of individuals with atopic dermatitis.
OBJECTIF: La dermatite atopique (DA) est caractérisée par des modifications de la composition et de la structure de la peau au niveau des sites lésionnels. L'altération des taux et de l'organisation des composants protéiques et lipidiques est associée au statut de la maladie, et entraîne une altération de la barrière et de l'hydratation. La cornéodesmosine (CDSN), et la disposition et la longueur des lamelles lipidiques intercellulaires (LLIC) sont altérées dans les états cutanés perturbés. L'objectif de cette étude était d'établir le profil de la distribution de la CDSN et des LLIC dans la couche cornée (CC) au niveau des sites lésionnels et non lésionnels dans la peau sujette à la DA, et d'étudier l'impact d'une lotion apaisante contre l'eczéma contenant de la vaseline, des acides gras et de l'avoine colloïdale. MÉTHODES: Une étude approuvée par un CPP a été menée auprès de participants atteints de DA active. Dans un petit sousensemble de participants, des bandes adhésives ont été prélevées sur des sites lésionnels et non lésionnels du bras, avant et après l'application deux fois par jour pendant 4 semaines d'une lotion apaisante contre l'eczéma contenant de la vaseline, des acides gras et de l'avoine colloïdale. Une coloration par anticorps fluorescents a été utilisée pour étudier la distribution de la CDSN. La microscopie électronique en transmission (MET) a été utilisée pour caractériser les LLIC. RÉSULTATS: La distribution/couverture de la CDSN était similaire entre les sites lésionnels et non lésionnels à l'entrée dans l'étude; l'application de la lotion a entraîné une distribution en nid d'abeille/périphérique plus définie. Le taux normalisé de LLIC (LLICn) était plus faible dans les échantillons prélevés à l'entrée dans l'étude au niveau des sites lésionnels par rapport aux sites non lésionnels. L'application de la lotion a augmenté ce paramètre à la fin de l'étude pour tous les sites. CONCLUSIONS: La lotion apaisante contre l'eczéma contenant de la vaseline, des acides gras et de l'avoine colloïdale a entraîné des changements dans la distribution des protéines cornéodesmosomales et des LLIC, ce qui correspond à des améliorations de la maturation des cornéocytes et de la fonction de barrière de la peau des personnes atteintes de dermatite atopique.
Subject(s)
Dermatitis, Atopic , Humans , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/metabolism , Dermatitis, Atopic/pathology , Adult , Male , Female , Glycoproteins/pharmacology , Intercellular Signaling Peptides and Proteins/metabolism , Lipids/chemistry , Eczema/drug therapy , Eczema/pathology , Eczema/metabolism , Skin Cream , Young Adult , Epidermis/metabolism , Epidermis/drug effects , Epidermis/pathology , Middle AgedABSTRACT
Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by increased sensitivity to environmental allergens and irritants. Icariin, a natural compound extracted from the herb Epimedium, has been traditionally used for its potential anti-inflammatory and antioxidant properties. This study aimed to investigate the regulatory effects of icariin on AD-like symptoms and to elucidate its underlying mechanisms. The effects of icariin on TNF-α/IFN-γ-induced HaCaT cell injury were assessed using various assays, including cell counting kit-8 for cell viability, flow cytometry for reactive oxygen species (ROS) levels, and colorimetric assays for malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity. In addition, the study performed enzyme-linked immunosorbent assays to assess cytokines (IL-1ß, IL-6, and IL-8) and chemokines (MDC, TARC, and RANTES) levels. Flow cytometry was used to quantify apoptotic rate, while a wound-healing assay was conducted to assess cell migration. The expression of WT1 associated protein (WTAP) and serpin family B member 4 (SERPINB4) at the mRNA and protein levels was determined using qRT-PCR and western blotting, respectively. The associations between WTAP and SERPINB4 were analyzed using RNA immunoprecipitation assay and m6A RNA immunoprecipitation assay. Icariin treatment significantly mitigated TNF-α/IFN-γ-induced oxidative stress, inflammatory response, and apoptosis in HaCaT cells, while also reversing the inhibitory effect on cell migration. Icariin reduced the expression of WTAP in TNF-α/IFN-γ-stimulated HaCaT cells. Overexpression of WTAP reversed the effects of icariin in TNF-α/IFN-γ-stimulated HaCaT cells. WTAP silencing inhibited the mRNA stability of SERPINB4 through the m6A modification. SERPINB4 overexpression attenuated the effects of WTAP silencing on oxidative stress, inflammatory response, apoptosis, and migration of TNF-α/IFN-γ-stimulated HaCaT cells. Icariin treatment downregulated SERPINB4 expression by regulating WTAP in TNF-α/IFN-γ-stimulated HaCaT cells. Icariin ameliorated TNF-α/IFN-γ-induced human immortalized epidermal cell injury through the WTAP/SERPINB4 axis, highlighting the potential for targeted interventions in AD pathogenesis.
Subject(s)
Apoptosis , Dermatitis, Atopic , Flavonoids , HaCaT Cells , Interferon-gamma , Oxidative Stress , Tumor Necrosis Factor-alpha , Humans , Flavonoids/pharmacology , Oxidative Stress/drug effects , Apoptosis/drug effects , Tumor Necrosis Factor-alpha/metabolism , Interferon-gamma/metabolism , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/pathology , Dermatitis, Atopic/metabolism , Serpins/metabolism , Keratinocytes/drug effects , Keratinocytes/metabolism , Cell Survival/drug effects , Signal Transduction/drug effects , Reactive Oxygen Species/metabolism , Cell Movement/drug effects , Antioxidants/pharmacology , Anti-Inflammatory Agents/pharmacology , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , Cytokines/metabolismABSTRACT
Graphene oxide (GO), a carbon-based material with oxygen-containing functional groups, can be applied in biomedicine for drug delivery, cancer therapy, and tissue regeneration. We have previously shown that nanoscale-sized graphene oxide (NGO), an oxidized graphene derivative, exhibits effective anti-inflammatory activity in a murine model of sepsis mediated by T helper (Th)1-promoting cytokines such as IFNγ and TNFα. However, whether NGO influences Th2-induced skin inflammation remains unclear. To address this issue, we employed an ovalbumin (OVA) plus aluminum hydroxide (Alum)-induced Th2-mediated skin inflammation model in conjunction with OVA-specific DO11.10 T cell receptor transgenic Balb/c mice. In vivo NGO injection upon OVA/Alum sensitization down-regulated OVA-elicited antigen-specific Th2 cells and GATA3-expressing Th2-type regulatory T cells. Next, we examined the effect of NGO injection on OVA/Alum-induced atopic dermatitis (AD)-like skin inflammation. NGO-injected mice exhibited significantly decreased Th2 disease phenotypes (e.g., a lower clinical score, decreased epidermal thickness and Th2 cell differentiation, and fewer infiltrated mast cells and basophils in skin lesions) compared with vehicle-injected control mice. Overall, our results suggest that NGOs are promising therapeutic materials for treating allergic diseases such as AD.
Subject(s)
Graphite , Mice, Inbred BALB C , Ovalbumin , Th2 Cells , Animals , Graphite/chemistry , Th2 Cells/immunology , Th2 Cells/drug effects , Mice , Alum Compounds/chemistry , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/chemically induced , Dermatitis, Atopic/pathology , Dermatitis, Atopic/immunology , Female , Inflammation/drug therapy , Inflammation/pathology , Inflammation/chemically induced , Down-Regulation/drug effects , Skin/drug effects , Skin/pathology , Skin/immunology , Nanoparticles/chemistryABSTRACT
Atopic dermatitis (AD) is a common allergic inflammatory skin condition marked by severe itching, skin lichenification, and chronic inflammation. AD results from a complex immune response, primarily driven by T lymphocytes and environmental triggers, leading to a disrupted epidermal barrier function. Traditional treatments, such as topical corticosteroids, have limitations due to long-term side effects, highlighting the need for safer alternatives. Here, we aimed to show that Agrimonia coreana extract (ACext) can be used in treating AD-related dermatologic symptoms. ACext could inhibit CRAC (Calcium Release-Activated Calcium) channel activity, reducing Orai1/CRAC currents and decreasing intracellular calcium signaling. This inhibition was further confirmed by the reduced IL-2 levels and T cell proliferation upon ACext treatment. In a mouse model of AD, ACext significantly ameliorates symptoms, improves histological parameters, and enhances skin barrier function, demonstrating its potential for treating AD.
Subject(s)
Agrimonia , Dermatitis, Atopic , Plant Extracts , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/metabolism , Dermatitis, Atopic/pathology , Animals , Plant Extracts/pharmacology , Plant Extracts/chemistry , Plant Extracts/therapeutic use , Mice , Agrimonia/chemistry , Disease Models, Animal , Calcium Release Activated Calcium Channels/metabolism , Calcium Release Activated Calcium Channels/antagonists & inhibitors , Humans , Calcium Channel Blockers/pharmacology , Calcium Channel Blockers/therapeutic use , Calcium Signaling/drug effects , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism , T-Lymphocytes/immunologyABSTRACT
Increasing evidence suggests an association between atopic dermatitis, the most chronic inflammatory disease of the skin, and autism spectrum disorders, which are a group of neurodevelopmental diseases. Inflammation and immune dysregulation associated with genetic and environmental factors seem to characterize the pathophysiological mechanisms of both conditions. We conducted a literature review of the PubMed database aimed at identifying the clinical features and alleged risk factors that could be used in clinical practice to predict the onset of ASD and/or AD or worsen their prognosis in the context of comorbidities.
Subject(s)
Autism Spectrum Disorder , Dermatitis, Atopic , Dermatitis, Atopic/etiology , Dermatitis, Atopic/pathology , Humans , Autism Spectrum Disorder/etiology , Autism Spectrum Disorder/epidemiology , Risk Factors , ComorbidityABSTRACT
Caspase recruitment domain family member 14 (CARD14) and its variants are associated with both atopic dermatitis (AD) and psoriasis, but their mechanistic impact on skin barrier homeostasis is largely unknown. CARD14 is known to signal via NF-κB; however, CARD14-NF-κB signaling does not fully explain the heterogeneity of CARD14-driven disease. Here, we describe a direct interaction between CARD14 and MYC and show that CARD14 signals through MYC in keratinocytes to coordinate skin barrier homeostasis. CARD14 directly binds MYC and influences barrier formation in an MYC-dependent fashion, and this mechanism is undermined by disease-associated CARD14 variants. These studies establish a paradigm that CARD14 activation regulates skin barrier function by two distinct mechanisms, including activating NF-κB to bolster the antimicrobial (chemical) barrier and stimulating MYC to bolster the physical barrier. Finally, we show that CARD14-dependent MYC signaling occurs in other epithelia, expanding the impact of our findings beyond the skin.
Subject(s)
CARD Signaling Adaptor Proteins , Epidermis , Homeostasis , Keratinocytes , NF-kappa B , Proto-Oncogene Proteins c-myc , Humans , CARD Signaling Adaptor Proteins/metabolism , CARD Signaling Adaptor Proteins/genetics , Proto-Oncogene Proteins c-myc/metabolism , Proto-Oncogene Proteins c-myc/genetics , Epidermis/metabolism , Keratinocytes/metabolism , NF-kappa B/metabolism , Signal Transduction , Dermatitis, Atopic/metabolism , Dermatitis, Atopic/pathology , Dermatitis, Atopic/genetics , Guanylate Cyclase/metabolism , Guanylate Cyclase/genetics , Epithelium/metabolism , Protein Binding , Psoriasis/metabolism , Psoriasis/genetics , Psoriasis/pathology , Membrane ProteinsABSTRACT
Atopic dermatitis (AD) presents significant therapeutic challenges due to its poorly understood etiology. Eosinophilia, a hallmark of allergic inflammation, is implicated in AD pathogenesis. Interleukin-10 (IL-10)-producing regulatory B (Breg) cells exhibit potent anti-inflammatory effects. However, their role in controlling AD-related eosinophilia is not well understood. To investigate the impact of eosinophils on AD, we employed IL-5Rα-deficient (Il5ra-/-) mice, which lack functional eosinophils. Induction of AD in these mice resulted in attenuated disease symptoms, underscoring the critical role of eosinophils in AD development. Additionally, the adoptive transfer of purified Breg cells into mice with AD significantly alleviated disease severity. Mechanistic studies revealed that IL-10 produced by Breg cells directly inhibits eosinophil activation and infiltration into the skin. In vitro experiments further confirmed that Breg cells inhibited eosinophil peroxidase secretion in an IL-10-dependent manner. Our collective findings demonstrate that IL-10 from Breg cells alleviates AD by suppressing eosinophil activation and tissue infiltration. This study elucidates a novel regulatory mechanism of Breg cells, providing a foundation for future Breg-mediated therapeutic strategies for AD.
Subject(s)
B-Lymphocytes, Regulatory , Dermatitis, Atopic , Eosinophils , Interleukin-10 , Animals , Dermatitis, Atopic/immunology , Dermatitis, Atopic/therapy , Dermatitis, Atopic/pathology , Dermatitis, Atopic/metabolism , Interleukin-10/metabolism , Eosinophils/immunology , Eosinophils/metabolism , B-Lymphocytes, Regulatory/immunology , B-Lymphocytes, Regulatory/metabolism , Mice , Mice, Knockout , Mice, Inbred C57BL , Disease Models, Animal , Skin/pathology , Skin/immunology , Skin/metabolism , Adoptive TransferABSTRACT
The clinical manifestations of atopic dermatitis (AD) and chronic nodular prurigo (CNPG) include pruritus and eczema/lesions, posing significant challenges for patients. Th2 cells and ILC2, marked by cytokine production-particularly IL-4/13-are crucial therapeutic targets. Despite displaying a dose-dependent lack of pruritus induction post-injection, IL-13 acts through the IL-13Rα1 and IL-13Rα2 receptor system. Our study focused on investigating ex vivo skin biopsies in AD (n = 17), CNPG (n = 14) and healthy controls (HC; n = 10), examining the gene expression landscape of interleukins linked with pruritus (IL-13, IL-4, IL-31) and their corresponding receptors. Compared to HC, results revealed a significant upregulation of IL-4, IL-13, and IL-13RA1 in AD, whereas CNPG did not show increased IL13 expression. Notably, the decoy receptor IL-13RA2 displayed intriguing patterns, with AD showing a marked increase compared to both HC and CNPG. Positive correlations between receptor expression and itch intensity and hyperkinesis sensation underscore clinical relevance, potentially serving as biomarkers. The findings suggest a pivotal role of IL-4 and IL-13, along with IL-13RA1, in pruritus pathogenesis in both entities, while IL-13 upregulation in AD is countered by IL-13RA2. The comparable expression of IL-13RA2 to HC in CNPG suggests the absence of this regulatory mechanism, potentially worsening the disease and leading to prolonged scratching behavior. These insights illuminate the intricate interplay of interleukins and receptors in different pruritus phenotypes, laying the groundwork for understanding underlying mechanisms and offering avenues for therapeutic intervention.
Subject(s)
Dermatitis, Atopic , Interleukin-13 , Interleukins , Prurigo , Pruritus , Humans , Dermatitis, Atopic/metabolism , Dermatitis, Atopic/genetics , Dermatitis, Atopic/pathology , Dermatitis, Atopic/immunology , Prurigo/metabolism , Prurigo/pathology , Prurigo/genetics , Female , Adult , Male , Interleukin-13/metabolism , Interleukin-13/genetics , Interleukins/metabolism , Interleukins/genetics , Pruritus/metabolism , Pruritus/genetics , Middle Aged , Interleukin-4/metabolism , Interleukin-4/genetics , Chronic Disease , Skin/metabolism , Skin/pathology , Young Adult , Interleukin-13 Receptor alpha1 Subunit/metabolism , Interleukin-13 Receptor alpha1 Subunit/genetics , Interleukin-13 Receptor alpha2 Subunit/metabolism , Interleukin-13 Receptor alpha2 Subunit/geneticsABSTRACT
Atopic skin is dry and itchy and lacks integrity. Impaired skin barrier results from altered lipid composition of the skin. A crucial skin lipid, cholesterol, provides flexibility and homeostasis of the cell membranes' lipid bilayer. Cholesterol-based creams and natural oils, especially blackcurrant seed oil, are beneficial for skin care as they hydrate the skin and improve its integrity. The major atopic symptom, skin dryness, can be overcome by the application of porous patches enhanced with cholesterol and natural oil. The base of the patches is constructed of polyimide (PI) nanofibers with cholesterol coatings and externally added blackcurrant seed oil. The presence of cholesterol in PI mats hinders the passage of oil through the patches to the skin, resulting in sustained and prolonged skin hydration. The theoretical and numerical investigations of oil dynamics in porous mats confirmed the experimental results, showing a prolonged skin hydration effect up to 6 h. Additionally, as demonstrated by in vivo tests on atopic mice, cholesterol patches lower serum immunoglobulin E levels and expression of proinflammatory cytokines in the skin, thereby accelerating skin healing. Our results hold great promise for the long-term application of the patches in atopic dermatitis treatment.
Subject(s)
Cholesterol , Dermatitis, Atopic , Nanofibers , Skin , Cholesterol/chemistry , Nanofibers/chemistry , Animals , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/pathology , Mice , Skin/drug effects , Skin/metabolism , Skin/pathology , Inflammation/drug therapy , Plant Oils/chemistry , Plant Oils/pharmacology , HumansABSTRACT
Atopic dermatitis (AD), a prevalent chronic inflammatory disease with multifactorial etiology, features epidermal barrier defects and immune overactivation. Synthetic glucocorticoids (GCs) are widely prescribed for treating AD due to their anti-inflammatory actions; however, mechanisms are incompletely understood. Defective local GC signaling due to decreased production of endogenous ligand and/or GC receptor (GR) levels was reported in prevalent inflammatory skin disorders; whether this is a consequence or contributing factor to AD pathology is unclear. To identify the chromatin-bound cell-type-specific GR protein interactome in keratinocytes, we used rapid immunoprecipitation of endogenous proteins and mass spectrometry identifying 145 interactors that increased upon dexamethasone treatment. GR-interacting proteins were enriched in p53/p63 signaling, including epidermal transcription factors with critical roles in AD pathology. Previous analyses indicating mirrored AD-like phenotypes between P63 overexpression and GR loss in epidermis, and our data show an intricate relationship between these transcription factors in human keratinocytes, identifying TP63 as a direct GR target. Dexamethasone treatment counteracted transcriptional up-regulation of inflammatory markers by IL4/IL13, known to mimic AD, causing opposite shifts in GR and P63 genomic binding. Indeed, IL4/IL13 decreased GR and increased P63 levels in cultured keratinocytes and human epidermal equivalents (HEE), consistent with GR down-regulation and increased P63 expression in AD lesions vs normal skin. Moreover, GR knockdown (GRKD) resulted in constitutive increases in P63, phospho-P38 and S100A9, IL6, and IL33. Also, GRKD culture supernatants showed increased autocrine production of TH2-/TH1-/TH17-TH22-associated factors including IL4, CXCL10, CXCL11, and CXCL8. GRKD HEEs showed AD-like features including hyperplasia and abnormal differentiation, resembling phenotypes observed with GR antagonist or IL4/IL13 treatment. The simultaneous GR/P63 knockdown partially reversed constitutive up-regulation of inflammatory genes in GRKD. In summary, our data support a causative role for GR loss in AD pathogenesis via functional interactions with P63 and autocrine signaling in epidermal keratinocytes.
Subject(s)
Autocrine Communication , Dermatitis, Atopic , Dexamethasone , Keratinocytes , Receptors, Glucocorticoid , Keratinocytes/metabolism , Keratinocytes/pathology , Humans , Dermatitis, Atopic/pathology , Dermatitis, Atopic/metabolism , Dermatitis, Atopic/genetics , Receptors, Glucocorticoid/metabolism , Dexamethasone/pharmacology , Epidermis/metabolism , Epidermis/pathology , Inflammation/pathology , Inflammation/metabolism , Transcription Factors/metabolism , Transcription Factors/genetics , Signal Transduction , Tumor Suppressor Proteins/metabolism , Tumor Suppressor Proteins/geneticsABSTRACT
Sinomenine hydrochloride is an excellent drug with anti-inflammatory, antioxidant, immune-regulatory, and other functions. Atopic dermatitis is an inherited allergic inflammation that causes itchiness, redness, and swelling in the affected area, which can have a significant impact on the life of the patient. There are many therapeutic methods for atopic dermatitis, and sinomenine with immunomodulatory activity might be effective in the treatment of atopic dermatitis. In this study, the atopic dermatitis model was established in experimental mice, and physical experiments were carried out on the mice. In the experiment, sinomenine hydrochloride liposomes-in-hydrogel as a new preparation was selected for delivery. In this case, liposomes were dispersed in the colloidal hydrogel on a mesoscopic scale and could provide specific transfer properties. The results showed that the sinomenine hydrochloride-loaded liposomes-in-hydrogel system could effectively inhibit atopic dermatitis.
Subject(s)
Antioxidants , Dermatitis, Atopic , Hydrogels , Liposomes , Morphinans , Morphinans/pharmacology , Morphinans/chemistry , Morphinans/therapeutic use , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/pathology , Liposomes/chemistry , Animals , Mice , Antioxidants/pharmacology , Antioxidants/chemistry , Antioxidants/administration & dosage , Hydrogels/chemistry , Disease Models, Animal , Male , Mice, Inbred BALB CABSTRACT
Atopic dermatitis (AD) is a chronic inflammatory skin condition with complex causes involving immune factors. The presence of essential trace elements that support immune system function can influence the development of this condition. This study investigated how serum trace elements impact the pathogenesis of atopic dermatitis. Upon analyzing serum microelements in AD patients and control subjects, it was observed that patients with AD had notably lower zinc levels. Genomic analysis of AD skin revealed distinct gene expression patterns, specifically the increased expression of CXCL10 in the epidermis. The heightened levels of CXCL10 in AD skin lesions were found to correlate with reduced serum zinc levels. Treatment with zinc gluconate showed reduced chemotactic response and CXCL10 release, suggesting its potential to regulate CXCL10 expression of keratinocytes in AD. The mechanism behind this involved the downregulation of STAT phosphorylation through activating PPARα. In the AD-like dermatitis mouse model, zinc gluconate therapy decreased serum IgE levels, alleviated skin lesion severity, reduced skin thickness, and lowered CXCL10 expression, demonstrating its efficacy in managing AD-like skin conditions. These findings indicate that zinc gluconate can reduce inflammation in keratinocytes by activating PPARα, inhibiting STAT signaling, and decreasing CXCL10 release, thus highlighting its potential as a therapeutic target for AD.
Subject(s)
Chemokine CXCL10 , Dermatitis, Atopic , Gluconates , Keratinocytes , PPAR alpha , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/pathology , Keratinocytes/drug effects , Keratinocytes/metabolism , Chemokine CXCL10/metabolism , Animals , Humans , Gluconates/pharmacology , PPAR alpha/metabolism , Male , Female , Mice , Adult , Skin/drug effects , Skin/pathology , Skin/metabolism , Disease Models, Animal , Mice, Inbred BALB C , Signal Transduction/drug effectsABSTRACT
Chronic exposure to harmful pollutants, chemicals, and pathogens from the environment can lead to pathological changes in the epithelial barrier, which increase the risk of developing an allergy. During allergic inflammation, epithelial cells send proinflammatory signals to group 2 innate lymphoid cell (ILC2s) and eosinophils, which require energy and resources to mediate their activation, cytokine/chemokine secretion, and mobilization of other cells. This review aims to provide an overview of the metabolic regulation in allergic asthma, atopic dermatitis (AD), and allergic rhinitis (AR), highlighting its underlying mechanisms and phenotypes, and the potential metabolic regulatory roles of eosinophils and ILC2s. Eosinophils and ILC2s regulate allergic inflammation through lipid mediators, particularly cysteinyl leukotrienes (CysLTs) and prostaglandins (PGs). Arachidonic acid (AA)-derived metabolites and Sphinosine-1-phosphate (S1P) are significant metabolic markers that indicate immune dysfunction and epithelial barrier dysfunction in allergy. Notably, eosinophils are promoters of allergic symptoms and exhibit greater metabolic plasticity compared to ILC2s, directly involved in promoting allergic symptoms. Our findings suggest that metabolomic analysis provides insights into the complex interactions between immune cells, epithelial cells, and environmental factors. Potential therapeutic targets have been highlighted to further understand the metabolic regulation of eosinophils and ILC2s in allergy. Future research in metabolomics can facilitate the development of novel diagnostics and therapeutics for future application.
Subject(s)
Hypersensitivity , Humans , Hypersensitivity/metabolism , Hypersensitivity/immunology , Animals , Eosinophils/metabolism , Eosinophils/immunology , Epithelial Cells/metabolism , Epithelial Cells/immunology , Immunity, Innate , Dermatitis, Atopic/immunology , Dermatitis, Atopic/metabolism , Dermatitis, Atopic/pathology , Lymphocytes/metabolism , Lymphocytes/immunology , Rhinitis, Allergic/metabolism , Rhinitis, Allergic/immunologyABSTRACT
BACKGROUND: Inflammatory skin diseases, such as psoriasis, atopic eczema, and contact dermatitis pose diagnostic challenges due to their diverse clinical presentations and the need for rapid and precise diagnostic assessment. OBJECTIVE: While recent studies described non-invasive imaging devices such as Optical coherence tomography and Line-field confocal OCT (LC-OCT) as possible techniques to enable real-time visualization of pathological features, a standardized analysis and validation has not yet been performed. METHODS: One hundred forty lesions from patients diagnosed with atopic eczema (57), psoriasis (50), and contact dermatitis (33) were imaged using OCT and LC-OCT. Statistical analysis was employed to assess the significance of their characteristic morphologic features. Additionally, a decision tree algorithm based on Gini's coefficient calculations was developed to identify key attributes and criteria for accurately classifying the disease groups. RESULTS: Descriptive statistics revealed distinct morphologic features in eczema, psoriasis, and contact dermatitis lesions. Multivariate logistic regression demonstrated the significance of these features, providing a robust differentiation between the three inflammatory conditions. The decision tree algorithm further enhanced classification accuracy by identifying optimal attributes for disease discrimination, highlighting specific morphologic criteria as crucial for rapid diagnosis in the clinical setting. CONCLUSION: The combined approach of descriptive statistics, multivariate logistic regression, and a decision tree algorithm provides a thorough understanding of the unique aspects associated with each inflammatory skin disease. This research offers a practical framework for lesion classification, enhancing the interpretability of imaging results for clinicians.
Subject(s)
Dermatitis, Atopic , Psoriasis , Tomography, Optical Coherence , Humans , Tomography, Optical Coherence/methods , Psoriasis/diagnostic imaging , Psoriasis/pathology , Dermatitis, Atopic/diagnostic imaging , Dermatitis, Atopic/pathology , Algorithms , Female , Male , Dermatitis, Contact/diagnostic imaging , Dermatitis, Contact/pathology , Adult , Skin/diagnostic imaging , Skin/pathology , Middle Aged , Diagnosis, Differential , Reproducibility of ResultsABSTRACT
Celastrol, a bioactive molecule extracted from the plant Tripterygium wilfordii Hook F., possesses anti-inflammatory, anti-obesity and anti-tumour properties. Despite its efficacy in improving erythema and scaling in psoriatic mice, the specific therapeutic mechanism of celastrol in atopic dermatitis (AD) remains unknown. This study aims to examine the role and mechanism of celastrol in AD using TNF-α-stimulated HaCaT cells and DNCB-induced Balb/c mice as in vitro and in vivo AD models, respectively. Celastrol was found to inhibit the increased epidermal thickness, reduce spleen and lymph node weights, attenuate inflammatory cell infiltration and mast cell degranulation and decrease thymic stromal lymphopoietin (TSLP) as well as various inflammatory factors (IL-4, IL-13, TNF-α, IL-5, IL-31, IL-33, IgE, TSLP, IL-17, IL-23, IL-1ß, CCL11 and CCL17) in AD mice. Additionally, celastrol inhibited Ezrin phosphorylation at Thr567, restored mitochondrial network structure, promoted translocation of Drp1 to the cytoplasm and reduced TNF-α-induced cellular reactive oxygen species (ROS), mitochondrial ROS (mtROS) and mitochondrial membrane potential (MMP) production. Interestingly, Mdivi-1 (a mitochondrial fission inhibitor) and Ezrin-specific siRNAs lowered inflammatory factor levels and restored mitochondrial reticular formation, as well as ROS, mtROS and MMP production. Co-immunoprecipitation revealed that Ezrin interacted with Drp1. Knocking down Ezrin reduced mitochondrial fission protein Drp1 phosphorylation and Fis1 expression while increasing the expression of fusion proteins Mfn1 and Mfn2. The regulation of mitochondrial fission and fusion by Ezrin was confirmed. Overall, celastrol may alleviate AD by regulating Ezrin-mediated mitochondrial fission and fusion, which may become a novel therapeutic reagent for alleviating AD.