The Implications of Pruritogens in the Pathogenesis of Atopic Dermatitis.
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ABSTRACT:
SUBMITTER: Wong LS
PROVIDER: S-EPMC8269281 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Atopic dermatitis is a chronic, non-infectious inflammatory dermatosis. Acharacteristic feature is persistent itching of the skin. The chronic, relapsing course of the disease, economic burden, and the whole family's involvement in the treatment process immensely reduce the quality of life of patients and their families. The disease emerges as a social problem by increasing indirect costs, such as visiting a doctor, absenteeism from work and school, and avoiding social interactions. Thepathophysiology of atopic dermatitis is complex and multifactorial. It includes genetic disorders, a defect in the epidermal barrier, an altered immune response, anddisruption of the skin's microbial balance. The numerous complex changes at thegenetic level and innate and adaptive immunity provide the basis for characterizing the various phenotypes and endotypes of atopic dermatitis. Emerging therapies rely on the action of specific molecules involved in the disease's pathogenesis. It may be the starting point for the individualization of atopic dermatitis treatment. This paper will try to present some molecular mechanisms of atopic dermatitis and their clinical implications.
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Project description:Atopic dermatitis (AD) is the most common chronic inflammatory skin disease. Genetic predisposition, epidermal barrier disruption, and dysregulation of the immune system are some of the critical components of AD. An impaired skin barrier may be the initial step in the development of the atopic march as well as AD, which leads to further skin inflammation and allergic sensitization. Type 2 cytokines as well as interleukin 17 and interleukin 22 contribute to skin barrier dysfunction and the development of AD. New insights into the pathophysiology of AD have focused on epidermal lipid profiles, neuroimmune interactions, and microbial dysbiosis. Newer therapeutic strategies focus on improving skin barrier function and targeting polarized immune pathways found in AD. Further understanding of AD pathophysiology will allow us to achieve a more precision medicine approach to the prevention and the treatment of AD.
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Project description:Atopic dermatitis (AD) is one of the most common and most intensively studied chronic inflammatory skin diseases. Several cofactors, such as an impaired skin barrier function, modifications of the immune system, and a complex genetic background, direct the course of AD. Within this complex network, macrophages play a pivotal role in enhanced susceptibility to cutaneous infections and act as central connecting components in the pathogenesis of AD on the cellular level. In AD, macrophages are known to accumulate in acutely and chronically inflamed skin. During the early and short inflammatory phase, macrophages exert proinflammatory functions like antigen-presenting phagocytosis and the production of inflammatory cytokines and growth factors that facilitate the resolution of inflammation. However, persistence of pro-inflammatory activity and altered function of macrophages result in the development of chronic inflammatory diseases such as AD. The exact mechanism of macrophages activation in these processes is not yet completely understood. Further studies should be performed to clarify the dysregulated mechanism of macrophages activation in AD, and this would allow us to target these cells with versatile functions for therapeutic purpose and improve and control the disease. In this paper, we highlight the new findings on dysregulated function of macrophages and the importance of these cells in the pathogenesis of AD in general and the contribution of these cells in enhanced susceptibility against microbial infections in particular.
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Project description:Atopic dermatitis (AD) is a recurrent, chronic, and inflammatory skin disease, which processes with severe itchiness. It often coexists with different atopic diseases. The number of people suffering from AD is relatively high. Epidemiological research demonstrates that 15⁻30% of children and 2⁻10% adults suffer from AD. The disease has significant negative social and economic impacts, substantially decreasing the quality of life of the patients and their families. Thanks to enormous progress in science and technology, it becomes possible to recognise complex genetic, immunological, and environmental factors and epidermal barrier defects that play a role in the pathogenesis of AD. We hope that the new insight on cytokines in AD will lead to new, individualised therapy and will open different therapeutic possibilities. In this article, we will focus on the cytokines, interleukin (IL)-17, IL-19, IL-33, and TSLP (thymic stromal lymphopoietin), which play a significant role in AD pathogenesis and may become the targets for future biologic therapies in AD. It is believed that the new era of biological drugs in AD will give a chance for patients to receive more successful treatment.
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Project description:Atopic dermatitis (AD) is a chronic inflammatory skin disease of very high prevalence, especially in childhood, with no specific treatment or cure. As its pathogenesis is complex, multifactorial and not fully understood, further research is needed to increase knowledge and develop new targeted therapies. We have recently demonstrated the critical role of NAD+ and poly (ADP-ribose) (PAR) metabolism in oxidative stress and skin inflammation. Specifically, we found that hyperactivation of PARP1 in response to DNA damage induced by reactive oxygen species, and fueled by NAMPT-derived NAD+, mediated inflammation through parthanatos cell death in zebrafish and human organotypic 3D skin models of psoriasis. Furthermore, the aberrant induction of NAMPT and PARP activity was observed in the lesional skin of psoriasis patients, supporting the role of these signaling pathways in psoriasis and pointing to NAMPT and PARP1 as potential novel therapeutic targets in treating skin inflammatory disorders. In the present work, we report, for the first time, altered NAD+ and PAR metabolism in the skin of AD patients and a strong correlation between NAMPT and PARP1 expression and the lesional status of AD. Furthermore, using a human 3D organotypic skin model of AD, we demonstrate that the pharmacological inhibition of NAMPT and PARP reduces pathology-associated biomarkers. These results help to understand the complexity of AD and reveal new potential treatments for AD patients.
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Project description:Atopic dermatitis (AD) is a chronic and relapsing disease affecting an increasing number of patients. Usually starting in early childhood, AD can be the initial step of the so-called atopic march, i.e. followed by allergic rhinitis and allergic asthma. AD is a paradigmatic genetically complex disease involving gene-gene and gene-environment interactions. Genetic linkage analysis as well as association studies have identified several candidate genes linked to either the epidermal barrier function or to the immune system. Stress, bacterial or viral infections, the exposure to aero- or food-allergens as well as hygienic factors are discussed to aggravate symptoms of AD. Athough generalized Th2-deviated immune response is closely linked to the condition of AD, the skin disease itself is a biphasic inflammation with an initial Th2 phase and while chronic lesions harbour Th0/Th1 cells. Regulatory T cells have been shown to be altered in AD as well as the innate immune system in the skin. The main treatment-goals include the elimination of inflammation and infection, preserving and restoring the barrier function and controlling exacerbating factors. The overall future strategy in AD will be aimed to control skin inflammation by a more proactive management in order to potentially prevent the emergence of sensitization as well as to design customized management based on genetic and pathophysiologic information.
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Project description:Previous studies have demonstrated that microRNA (miR)‑146a is involved in the inflammatory response of atopic dermatitis (AD). The aim of the present study was to investigate the expression of miR‑146a in the serum of patients with AD and in skin lesions of AD animal models. In addition, we aimed to predict and verify the target genes of miR‑146a. miR‑146a expression was measured in AD patient serum via reverse transcription‑quantitative PCR. T‑helper (Th)1 [CD4+; interferon (IFN)‑γ+] and Th2 [CD4+; interleukin (IL)‑4+] expression in peripheral blood mononuclear cells was evaluated using flow cytometry. Following the establishment of a 2,4‑dinitrofluorobenzene‑induced C57BL/6 mouse AD model, Th1 (CD4+IFN‑γ+) and Th2 (CD4+IL‑4+) expression was analyzed in murine spleen cells via flow cytometry. Plasmids were transfected into 293T cells and at 48 h post‑transfection, cells were analyzed using a luciferase assay system. The results revealed that the AD group had a significantly lower Th1/Th2 ratio and a significantly higher miR‑146a expression compared with the control group (P<0.05). Furthermore, a decreased Th1/Th2 ratio and a significantly increased miR‑146a expression were observed in the model group compared with the control group (P<0.01). We also conducted a dual‑luciferase assay to determine whether small ubiquitin‑related modifier 1 (SUMO1) if the target gene of miR‑146a. We observed a ~30% decrease in the relative luciferase activity in cells containing the 3'‑untranslated region of SUMO1 + miR‑146a). The results of the luciferase assay indicated that may be a direct mRNA target of miR‑146a; however, the quantification of band density of SUMO1 expression following western blotting did not significantly differ. The development of animal models in AD research is of vital importance. The results revealed that miR‑146a may be a potential regulator involved in the pathogenesis of AD. Furthermore, the current study determined that miR‑146a could be a valuable marker of AD and thus, may be applied in the development of therapeutic strategies for treating AD.
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Project description:Atopic dermatitis (AD) is the most common inflammatory skin disease, and it is considered a complex and heterogeneous condition. Different phenotypes of AD, defined according to the patient age at onset, race, and ethnic background; disease duration; and other disease characteristics, have been recently described, underlying the need for a personalized treatment approach. Recent advancements in understanding AD pathogenesis resulted in a real translational revolution and led to the exponential expansion of the therapeutic pipeline. The study of biomarkers in clinical studies of emerging treatments is helping clarify the role of each cytokine and immune pathway in AD and will allow addressing the unique immune fingerprints of each AD subset. Personalized medicine will be the ultimate goal of this targeted translational research. In this review, we discuss the changes in the concepts of both the pathogenesis of and treatment approach to AD, highlight the scientific rationale behind each targeted treatment and report the most recent clinical efficacy data.
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Project description:Atopic dermatitis (AD) is a chronic skin condition with intense pruritus, eczema, and dry skin. The recurrent intense pruritus and numerous complications in patients with AD can profoundly affect their quality of life. Obesity is one of its comorbidities that has been confirmed to be the hazard factor of AD and also worsen its severity. Nevertheless, the specific mechanisms that explain the connection between obesity and AD remain incompletely recognized. Recent studies have built hopes on various adipokines to explain this connection. Adipokines, which are disturbed by an obese state, may lead to immune system imbalances in people with AD and promote the development of the disease. This review focuses on the abnormal expression patterns of adipokines in patients with AD and their potential regulatory molecular mechanisms associated with AD. The connection between AD and obesity is elucidated through the involvement of adipokines. This conduces to the in-depth exploration of AD pathogenesis and provides a new perspective to develop therapeutic targets.
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Project description:Atopic Dermatitis (AD) is the most common inflammatory skin disease and characterized by a deficient epidermal barrier and cutaneous inflammation. Genetic studies suggest a key role of keratinocytes in AD pathogenesis, but the alterations in the proteome that occur in the entire epidermis have not been defined. Employing a pressure-cycling technology-data-independent acquisition (PCT-DIA) approach, we performed quantitative proteomics of epidermis from healthy volunteers and lesional and non-lesional skin of AD patients. Results were validated by targeted proteomics using parallel reaction monitoring mass spectrometry or by immunofluorescence staining. The identified proteins reflect the strong inflammation in lesional skin and the defect in keratinocyte differentiation and epidermal stratification. Most importantly, they reveal impaired activation of the NRF2-antioxidant pathway and reduced abundance of mitochondrial proteins involved in key metabolic pathways in the epidermis. These results provide insight into the molecular alterations in the epidermis of AD patients and identify novel targets for pharmaceutical intervention.
2022-10-04 | PXD025431 | Pride