Cytokines In Atopic Dermatitis Research Articles

Potential Aspects of the Use of Cytokines in Atopic Dermatitis.

Atopic dermatitis (AD) is an abnormal inflammatory response in the skin to food, environmental IgE, or non-IgE allergens. This disease belongs to a group of inflammatory diseases that affect both children and adults. In highly developed countries, AD is diagnosed twice as often in children than in adults, which may possibly be connected to increased urbanization. The immune system's pathomechanisms of AD involve humoral mechanisms with IgE, cellular T lymphocytes, dendritic cells occurring in the dermis, Langerhans cells occurring in the epidermis, and other cells infiltrating the site of inflammation (eosinophils, macrophages, mast cells, neutrophils, and basophils). Cytokines are small proteins that affect the interaction and communication between cells. This review characterizes cytokines and potential aspects of the treatment of atopic dermatitis, as well as new strategies that are currently being developed, including targeting cytokines and their receptors.

IL-26 Potentiates Type 2 Skin Inflammation in the Presence of IL-1β

Atopic dermatitis (AD) is a debilitating inflammatory skin disorder. Biologics targeting the IL-4/IL-13 axis are effective in AD, but there is still a large proportion of patients that do not respond to IL-4R blockade. Further exploration of potentially pathogenic T cell-derived cytokines in AD may lead to new effective treatments. This study aimed to investigate the downstream effects of IL-26 on skin in the context of type 2 skin inflammation. We found that IL-26 alone exhibited limited inflammatory activity in skin. However, in presence of IL-1β, IL-26 potentiated the secretion of TSLP, CXCL1 and CCL20 from human epidermis through JAK/STAT signaling. Moreover, in an in vivo AD-like skin inflammation model, IL-26 exacerbated skin pathology and locally increased type 2 cytokines, most notably of Il13 in skin T helper cells. Neutralization of IL-1β abrogated IL-26-mediated effects, indicating that the presence of IL-1β is required for full IL-26 downstream action in vivo. These findings suggest that the presence of IL-1β enables IL-26 to be a key amplifier of inflammation in the skin. As such, IL-26 may contribute to the development and pathogenesis of inflammatory skin disorders such as AD.

The Interplay of Type 1, Type 2, and Type 3 Lymphocytes and Cytokines in Atopic Dermatitis

Atopic dermatitis (AD) is classified as a type 2 disease owing to the majority of type 2 lymphocytes that constitute the skin-infiltrating leukocytes. However, all of the type 1-3 lymphocytes intermingle in inflamed skin lesions. Here, using an AD mouse model where caspase-1 was specifically amplified under keratin-14 induction, we analyzed the sequential changes in type 1-3 inflammatory cytokines in lymphocytes purified from the cervical lymph nodes. Cells were cultured and stained for CD4, CD8, and γδTCR, followed by intracellular cytokines. Cytokine production in innate lymphocyte cells (ILCs) and the protein expression of type 2 cytokine IL-17E (IL-25) were investigated. We observed that, as inflammation progresses, the cytokine-producing T cells increased and abundant IL-13 but low levels of IL-4 are produced in CD4-positive T cells and ILCs. TNF-α and IFN-γ levels increased continuously. The total number of T cells and ILCs peaked at 4 months and decreased in the chronic phase. In addition, IL-25 may be simultaneously produced by IL-17F-producing cells. IL-25-producing cells increased in a time-dependent manner during the chronic phase and may work specifically for the prolongation of type 2 inflammation. Altogether, these findings suggest that inhibition of IL-25 may be a potential target in the treatment of inflammation.

Atopic dermatitis: Is innate or adaptive immunity in control? A clinical perspective.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with barrier defects and immune dysregulations. The pathogenesis of AD involves the physical barrier as well as epithelial cells, which are considered a vital part of the innate immunity of the skin. The importance of filaggrin mutations in the pathogenesis of AD has also been well-established with reproducible results around the world in multiple studies and ethnic groups. This protein plays an important role in skin barrier functions and further reaffirms barrier defects as one of the primary causes of AD. The main epithelial cells, keratinocytes, function as a major sentinel for the skin in detecting danger signals or microbial pathogens, and trigger downstream immune responses. In AD, these cells express TSLP, IL-33 and IL-25, which lead to downstream systemic production of type 2 cytokines. In spite of major advances in our understanding of the innate immunity of AD, recent success in the systemic therapeutics of AD have focused on targeting the products of the adaptive immunity, particularly cytokines produced by T cells. In addition to type 2 cytokines, type 17 cytokines have also been implicated in the pathogenesis of AD. The current review examines the implications of these cytokines in AD from clinical perspectives.

Dissolvable Microneedle Patch Increases the Therapeutic Effect of Jawoongo on DNCB-Induced Atopic Dermatitis in Mice

Background: Jawoongo (JW) is a topical herbal ointment that has been used as an alternative treatment option for atopic dermatitis. Topical ointments are known to have less bioavailability because the stratum corneum allows only lipophilic and low molecular weight drugs to pass across it. This study aimed to investigate whether applying microneedle patches (MNP) increases the therapeutic effect of 2,4-dinitrochlorobenzene (DNCB)+JW for atopic dermatitis by enhancing transdermal delivery. Methods: Atopic dermatitis was induced by DNCB in BALB/c mice. The combination treatment of JW and MNP was estimated to study the effect of MNP in improving transdermal delivery. Histological analysis, quantitative real-time PCR (qPCR), and immunofluorescence were performed to verify the effect of MNP in enhancing the therapeutic effects of DNCB+JW on atopic dermatitis in mice. Results: Both combination treatment and DNCB+JW treatment ameliorated histological alterations and reduced skin thickness and infiltration of CD4⁺ T cells in atopic dermatitis-like skin lesions in DNCB-exposed BALB/c mice. However, the improvement of histological alterations was better in the combination treatment, which was almost normal. Furthermore, the combination treatment exhibited a larger decrease in mRNA levels of IL-4, IL-6, IL-13, iNOS, and TNF-α, compared to DNCB+JW only. In addition, skin thickness and infiltration of CD4⁺ T cells in the sensitized skin were significantly lower using the combination treatment than using DNCB+JW only. Conclusion: Combination treatment with JW and MNP further decreased skin thickness and several inflammatory cytokines in atopic dermatitis like skin lesions compared to treatment using JW alone. These findings suggest that applying a dissolvable MNP after JW application could be useful for treating atopic dermatitis.

Multiple Roles for Cytokines in Atopic Dermatitis: From Pathogenic Mediators to Endotype-Specific Biomarkers to Therapeutic Targets.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, which generally presents with intense itching and recurrent eczematous lesions. AD affects up to 20% of children and 10% of adults in high-income countries. The prevalence and incidence of AD have increased in recent years. The onset of AD mostly occurs in childhood, although in some cases AD may persist in adult life or even manifest in middle age (adult-onset AD). AD pathophysiology is made of a complex net, in which genetic background, skin barrier dysfunction, innate and adaptive immune responses, as well as itch contribute to disease development, progression, and chronicization. One of the most important features of AD is skin dehydration, which is mainly caused by filaggrin mutations that determine trans-epidermal water loss, pH alterations, and antigen penetration. In accordance with the “outside-inside” theory of AD pathogenesis, in a context of an altered epidermal barrier, antigens encounter epidermal antigen presentation cells (APCs), such as epidermal Langerhans cells and inflammatory epidermal dendritic cells, leading to their maturation and Th-2 cell-mediated inflammation. APCs also bear trimeric high-affinity receptors for immunoglobulin E (IgE), which induce IgE-mediated sensitizations as part of pathogenic mechanisms leading to AD. In this review, we discuss the role of cytokines in the pathogenesis of AD, considering patients with various clinical AD phenotypes. Moreover, we describe the cytokine patterns in patients with AD at different phases of the disease evolution, as well as in relation to different phenotypes/endotypes, including age, race, and intrinsic/extrinsic subtypes. We also discuss the outcomes of current biologics for AD, which corroborate the presence of multiple cytokine axes involved in the background of AD. A deep insight into the correlation between cytokine patterns and the related clinical forms of AD is a crucial step towards increasingly personalized, and therefore more efficient therapy.

The role of cytokines in atopic dermatitis: a breakthrough in immunopathogenesis and treatment

Atopic dermatitis is a multifactorial inflammatory skin disease with a complex immunopathogenesis that is characterized by an underlying imbalance of T-cell subsets. Although cytokines of type 2 immunity consistently predominate in the acute phase of atopic dermatitis, there is strong evidence supporting the contribution of cytokines of type 1 immunity, type 3 immunity, and other cytokines in the development and progression of the disease. This review explores the cytokine network in atopic dermatitis, and it highlights areas and causes of controversy in the immunopathogenesis of the disease. In addition, it presents the current therapeutic targets currently being investigated, including monoclonal antibodies and small molecules that inhibit cytokines and downstream signaling molecules in atopic dermatitis. We conclude that atopic dermatitis has a complex and controversial cytokine profile. Understanding the role of cytokines in the immunopathogenesis of the disease is essential for identifying personalized targets for better management and disease control.

Role of Epithelium-Derived Cytokines in Atopic Dermatitis and Psoriasis: Evidence and Therapeutic Perspectives.

Atopic dermatitis and psoriasis are two of the most common chronic skin conditions. Current target therapies represent viable and safe solutions for the most severe cases of these two dermatoses but, presently, several limitations exist in terms of efficacy and side effects. A new class of products, epithelium-derived cytokines (TSLP, IL-25, IL-33), show an increasing potential for use in target therapy for these patients, and demonstrate a direct link between a generalized inflammatory and oxidative stress status and the human skin. A review was conducted to better understand their role in the aforementioned conditions. Of these three molecules, TSLP led has been most often considered in studies regarding target therapies, and most of the results in the literature are related to this cytokine. These three cytokines share common stimuli and are linked to each other in both acute and chronic phases of these diseases, and have been challenged as target therapies or biomarkers of disease activity. The results lead to the conclusion that epithelium-derived cytokines could represent a therapeutic opportunity for these patients, especially in itch control. Furthermore, they might work better when paired together with currently available therapies or in combination with in-development treatments. Further studies are needed in order to verify the efficacy and safety of the biologic treatments currently under development.

A Systemic Review of Dupilumab Efficacy and Safety by Phenotypic Variations of Atopic Dermatitis

Background: The Atopic Dermatitis (AD) is a chronic, pruritus- inflammatory TH2dominant skin disorder characterized by a reaction with complex immunopathogenesis. Dupilumab’s effectiveness and safety profile by phenotypic variations of atopic dermatitis the treatment of atopic dermatitis has been investigated in a variety of large clinical trials in atopic dermatitis for more than 10 years. The goal of the current systematic review was to determine the effectiveness and protection of dupilumab through phenotypic differences in atopic dermatitis. Methods: We systematically searched PubMed, MEDLINE, EMBASE and Google scholar databases to find appropriate articles published between last ten years related to dupilumab efficacy and safety by phenotypic variations of atopic dermatitis with the appropriate key terms (MeSH) including “dupilumab”, “atopic dermatitis”, “eczema”, “phenotypic variations” “phenotypes” etc. Results: Seven studies were included in the current review, which met the inclusion & exclusion criteria of the current study. All the included studies in this review demonstrated that the dupilumab significantly treated the various phenotypes of AD, with the improvement of EASI and DLQI scores. The most commonly occurred side effect during the treatment of duplimab was allergic conjunctivitis followed by allergic rhinitis and asthma. Most of the included studies demonstrated that the dupilumab has been shown to rapidly improving signs and symptoms in the treatment of extreme AD. Conclusion: Dupilumab was first prescribed for adults with atopic dermatitis and has been generally approved since 2018 for adult patients with moderate to extreme atopic dermatitis. The IL-4 and IL-13 cytokines in atopic dermatitis modulate the epidermal barrier and inhibit the production of antimicrobial peptides. Dupilumab’s efficacy and safety profile in the treatment of atopic dermatitis has been investigated in a number of major clinical trials. This current systematic review provides an evidence-based report on dupilumab efficacy and safety by different phenotypic variations of atopic dermatitis, which will help to clinicians for better understanding of the mechanism of dupilumab against AD phenotypes.

Cytokines and apoptosis in atopic dermatitis.

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease. AD affects 10–20% of children worldwide and persists into adulthood in a minority of cases, affecting approximately 2–3% of the adult population, with an increased prevalence over the past decades in developed countries. Atopy is a genetic tendency to overproduce IgE class antibodies in response to common antigens found in the environment. Concurrence of different atopy such as allergic rhinitis or asthma in children with AD is estimated at 80%. AD is characterized by a vicious cycle of an allergic immune response. The emerging picture of the AD is a complex disorder with barrier dysfunction, immunological, genetic and environmental factors all playing key roles. Patients with severe or persistent disease and their families experience significant impairment in their quality of life, and in addition, AD places a heavy economic burden on society as a whole. Pathogenesis, the role of the epidermal barrier, mechanisms of cells apoptosis, the role of T cells and cytokines in AD are discussed in this article.

The Role of Th17-Related Cytokines in Atopic Dermatitis

T helper-17 (Th17) cells, which mainly produce IL-17, are associated with development of various autoimmune diseases such as rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis, and psoriasis. IL-17 and related cytokines are therapeutic targets of these diseases. In atopic dermatitis (AD), Th2 cytokines such as IL-4 and IL-13 are regarded to be the main player of the disease; however, Th17 cytokines are also expressed in AD skin lesions. Expression of IL-22 rather than IL-17 is predominant in AD skin, which is contrary to cytokine expression in psoriasis skin. Relatively low IL-17 expression in AD skin can induce relatively low antimicrobial peptide expression, which may be a reason why bacterial infection is frequently seen in AD patients. Failure of clinical trials for investigating the efficacy of anti-IL-12/23 p40 in AD has suggested that IL-17 expressed in skin lesions should not be the main player but a bystander responding to barrier dysfunction.

New Cytokines in the Pathogenesis of Atopic Dermatitis-New Therapeutic Targets.

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.

A novel, topical, nonsteroidal, TRPV1 antagonist, PAC-14028 cream improves skin barrier function and exerts anti-inflammatory action through modulating epidermal differentiation markers and suppressing Th2 cytokines in atopic dermatitis

BackgroundAlthough it is established that epidermal barrier disturbance and immune dysfunction resulting in IgE sensitization are critical factors in the development of cutaneous inflammation, the pathogenesis and targeted therapy of atopic dermatitis (AD)-specific pathways have still been unknown. ObjectiveTaking into account the fact that Th2 cytokines in AD have both unique and overlapping functions including increased epidermal thickening, inflammation, and decreased expressing of the barrier proteins keratinocyte differentiation, we sought to clarify our hypothesis that TRPV1 antagonist plays a critical role in skin barrier function and can be a therapeutic target for AD. MethodsAD-like dermatitis was induced in hairless mice by repeated oxazolone (Ox) challenges to hairless mice. The functional studies concerning skin barrier function, anti-inflammatory action, and molecular mechanism by TRPV1 antagonism were conducted by histopathological assays, ELISA, qPCR, western blotting, and skin blood flow measurement. ResultsTopically administered TRPV1 antagonist, PAC-14028 (Asivatrep: C21H22F5N3O3S), improved AD-like dermatitis and skin barrier functions, and restored the expression of epidermal differentiation markers. In addition, the PAC-14028 cream significantly inhibited cutaneous inflammation by decreasing the expression of serum IgE, and the epidermal expression of IL-4, and IL-13 in Ox-AD mice. These results may provide a novel insight into the molecular mechanism of PAC-14028 cream involved in anti-inflammatory effects and skin barrier functions by suppressing the multiple signaling pathways including IL-4/-13-mediated activation of JAK/STAT, TRPV1, and neuropeptides. ConclusionPAC-14028 cream can be a potential therapeutic tool for the treatment of chronic inflammation and disrupted barrier function in patients with AD.

Topical application of Dermatophagoides farinae or oxazolone induces symptoms of atopic dermatitis in the rabbit ear.

Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disease characterized by hyperproliferation and abnormal differentiation of the epidermis, and dermal infiltration of inflammatory cells. Appropriate animal models that recapitulate human AD and allow the analysis of disease processes in a reliable manner are essential to the study of AD. In this study, we established two AD models in rabbits by applying an allergen, Dermatophagoides farinae (Der f), or a hapten, oxazolone (OXZ). Application of the allergen or hapten induced a rapid onset and a chronically sustained AD-like skin lesion. The clinical symptoms, which include skin erythema, scaling, papula and edema, of AD-like rabbit skin were similar to those in human AD. Histological analysis showed that allergen- or hapten-treated rabbit skin showed increased epidermal thickening and inflammatory cell infiltration. Furthermore, PCNA and keratin 10 (K10) staining revealed excessive proliferation and insufficient differentiation of the epidermis in the rabbit AD-like skin. Western blot analysis showed decreased expression of thymic stromal lymphopoietin (TSLP), an AD cytokine, in the rabbit AD-like skin. Our results suggest that the allergen- or hapten-induced rabbit AD models have pathological features of human AD-like symptoms and will be useful for evaluating both pathogenic mechanisms and potential therapeutic agents for human AD.

Characteristics of immune response and role of cytokines in atopic dermatitis

AD is a multifactorial disease, which is based on genetic disorders, immune mechanisms and influence of exogenous and endogenous factors. Study of immunopathogenesis of atopic dermatitis, it’s specific biomarkers, triggers is very important for understanding of causes and mechanisms of the disease as well as for developing of new methods of treatment. The review describes the current views on the immune response in AD.

Expression of vascular endothelial growth factor and other cytokines in atopic dermatitis, and correlation with clinical features

Vascular endothelial growth factor (VEGF) was found increased in the stratum corneum of patients with atopic dermatitis (AD). However, its potential pathogenic role(s) in AD needs further clarification. The aim of this study was to determine whether VEGF serum levels correlate with other selected cytokine levels and features of AD. VEGF and other cytokine levels were measured in 83 patients with AD and in a control group and then correlated with clinical and laboratory parameters of AD. The mean serum concentrations of VEGF and tumor necrosis factor α were significantly higher in patients with AD than in the control group, whereas the mean interleukin eight serum level was lower. VEGF concentrations correlated with the severity of AD as expressed by SCORAD index and objective SCORAD. VEGF could be regarded as a potentially important mediator in the pathogenesis of AD, as VEGF levels correlate somewhat with AD severity.

New insights into T cells and their signature cytokines in atopic dermatitis.

An imbalance of the adaptive immune system mediated by various T cells plays a pivotal role in the pathogenesis of atopic dermatitis (AD). Traditionally, sustained exposure of pathogens tailors immune responses and drives the development of specialized T helper (Th) 2-bias cytokine environment. The increasing understanding of T cell biology has refreshed the roles of classical Th2 responses and regulatory T cells in the development of AD. In particular, the identification of novel CD4(+) T cell subsets such as Th9, Th17, and Th22 cells provide further interpretation of immunological mechanisms underlying AD. In this report, we reviewed the functional roles of CD4(+) T cell subsets and their derived signature cytokines in AD. We focused on important discoveries of the contribution of CD4(+) T cell cytokines to immunomodulation in AD, and particularly, highlighted the multiple consequences of immune dysregulation on the barrier defect of the skin. We subsequently discussed the flexibility and plasticity of these T cells in vivo in terms of cytokine production. T cells involved in innate immunity were also mentioned. Taking the pivotal and varied roles of T-cell subpopulations and the functional cytokine milieus into account, T cell targeting therapy may thus open up new opportunities for mechanism-based therapeutic intervention.

Mutual upregulation of endothelin-1 and IL-25 in atopic dermatitis.

Endothelin-1 (ET-1) has been reported to evoke histamine-independent pruritus in mammals. However, its association with pruritus or inflammation of atopic dermatitis (AD) has not been clarified. We sought to investigate the role of ET-1 in the skin inflammation of AD. To examine the role of ET-1 in AD, we investigated the expression of ET-1 and IL-25 in the skin of an AD mouse model and patients with AD and examined the mutual regulatory relationship between ET-1 and IL-25, one of the important cytokines in AD, using the human HaCaT keratinocyte cell line. We immunohistochemically confirmed the upregulation of ET-1 and IL-25 expression in the epidermis of both the AD mouse model and patients with AD. In vitro, IL-25 upregulated ET-1 mRNA and protein expression in a concentration- and time-dependent fashion in HaCaT cells. This IL-25-induced ET-1 expression was inhibited by ERK1/2 or JNK inhibitor. In a reciprocal manner, ET-1 also induced IL-25 upregulation. The enhancing effect of ET-1 on IL-25 was inhibited by an endothelin A receptor antagonist, ERK1/2 inhibitor, or p38 inhibitor, but not by an endothelin B receptor antagonist or JNK inhibitor. These findings suggest that mutual upregulation of ET-1 and IL-25 takes place in the epidermis of AD, which may be a future target for antipruritic agents.

Interleukin-17 receptor A (IL-17RA) is a key regulator of type 2 inflammatory responses involved in maintaining immune system homeostasis. (IRC7P.431)

Abstract IL-17 cytokine family signaling is a key mediator of skin inflammatory disorders including atopic dermatitis and psoriasis. It has previously been shown that deficiency of IL-17 producing cells and especially TCRγδ T cells attenuates the skin inflammatory phenotype observed in murine models of psoriasis. Mice lacking IL-17 receptor A expression, through which IL-17A and other IL-17 family cytokines signal, develop severe and progressive skin inflammation. This spontaneous skin inflammation was characterized by increased epidermal thickness with cellular infiltration, which was accompanied with lymphadenopathy, and type 2 responses, including eosinophilia and increased serum levels of IgE. On a cellular level a significant increase in the numbers of innate lymphoid cell subpopulations was observed. Additionally IL-17RA-/- mice have increased γδ T cells with an activated memory-like phenotype. To further elucidate the role of IL-17 family cytokines in atopic dermatitis (AD) we crossed IL-17RA-/- mice with mice, carrying a mutation previously associated with human AD, that results in a spontaneous atopic dermatitis-like disease. The absence of IL-17RA signaling resulted in a severely accelerated AD like inflammation. This highlights that IL-17RA signaling is required for maintaining homeostasis including the regulation of Th2 responses.

Atopic dermatitis and alpha-chemokines.

Many studies have shown the involvement of interferon (IFN)γ-inducible protein 10 (IP-10) and T-helper 1 (Th1) cytokines in Atopic Dermatitis (AD). IFN-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-18 are potent stimulators of the expression and secretion of IP-10 in cultured keratinocytes from AD patients. Apoptosis of keratinocytes, induced mainly by T cells and mediated by IFN-γ, is the essential pathogenetic event in eczema formation. Enhanced IP-10, induced by IFN-γ, and IFN-inducible T cell alpha-chemoattractant (I-TAC) expression has been observed in lesional AD skin. It has been shown that keratinocytes undergoing apoptosis in acute eczematous lesions release chemokines that attract more T cells toward the epidermis, which may further augment the inflammation and keratinocyte apoptosis. Drugs used in the treatment of AD modulate IP-10. Antihistamines are widely used for the treatment of AD; it has been shown in human monocyte-derived dendritic cells (MoDCs) and autologous CD4+ T cells that antihistamines inhibited the production of IP-10 and�� monokine induced by IFN-gamma (MIG) expressions. It has been also shown that antimycotics and tacrolimus suppress the induced production of IP-10 in human keratinocytes.