Therapeutics For Atopic Dermatitis Research Articles

NLRP10 maintains epidermal homeostasis by promoting keratinocyte survival and P63-dependent differentiation and barrier function

Atopic dermatitis (AD) is a common chronic inflammatory skin disorder characterized by disrupted epidermal barrier function and aberrant immune responses. Despite recent developments in new therapeutics for AD, there is still a large unmet medical need for disease management due to the complex and multifactorial nature of AD. Recent genome-wide association studies (GWAS) have identified NLRP10 as a susceptible gene for AD but the physiological role of NLRP10 in skin homeostasis and AD remains unknown. Here we show that NLRP10 is downregulated in AD skin samples. Using an air-lift human skin equivalent culture, we demonstrate that NLRP10 promotes keratinocyte survival and is required for epidermal differentiation and barrier function. Mechanistically, NLRP10 limits cell death by preventing the recruitment of caspase-8 to the death inducing signaling complex (DISC) and by inhibiting its subsequent activation. NLRP10 also stabilizes p63, the master regulator of keratinocyte differentiation, to drive proper keratinocyte differentiation and to reinforce the barrier function. Our findings underscore NLRP10 as a key player in atopic dermatitis pathogenesis, highlighting NLRP10 as a potential target for therapeutic intervention to restore skin barrier function and homeostasis in AD.

The causal relationship between immune cells and atopic dermatitis: A bidirectional Mendelian randomization study.

Atopic dermatitis (AD) is a chronic inflammatory skin condition whose origins remain unclear. Existing epidemiological evidence suggests that inflammation and immune factors play pivotal roles in the onset and progression of AD. However, previous research on the connection between immune inflammation and AD has yielded inconclusive results. To evaluate the causal relationship between immunological characteristics and AD, this study employed a bidirectional, two-sample Mendelian randomization (MR) approach. We utilized large-scale, publicly available genome-wide association studies to investigate the causal associations between 731 immunological feature cells and the risk of AD. Significant associations were identified between six immune phenotypes and AD risk: increased Basophil %CD33dim HLA DR-CD66b-, CD25 on IgD+ CD24+, CD40 on monocytes, HLA DR on CD14+ CD16-monocytes, HLA DR on CD14+monocytes correlated with higher AD risk, while elevated CD3 on CD4 Treg was linked to lower risk. Reverse MR analysis revealed AD as a risk factor for IgD+ CD38br AC and IgD+ CD38br %B cell, but a protective factor against CD20 on IgD+ CD38- naive and CD8 on NKT. Our findings elucidate the intricate interplay between immune cells and AD, informing future research into AD pathophysiology and therapeutics.

Short-, mid- and long-term efficacy of dupilumab in moderate-to-severe atopic dermatitis: a real-world multicentre Italian study of 2576 patients

Abstract Background The efficacy and safety of dupilumab in atopic dermatitis (AD) have been defined in clinical trials but limited real-world evidence on long-term treatment outcomes is currently available to inform clinical decisions. Objectives To describe the long-term effectiveness and safety of dupilumab up to 48 months in patients with moderate-to-severe AD. Methods A multicentre, retrospective, dynamic cohort study was conducted to assess long-term effectiveness and safety of dupilumab in patients with moderate-to-severe AD in a real-world setting. Predictors of minimal disease activity (MDA) optimal treatment target criteria [defined as the simultaneous achievement of a 90% reduction in Eczema Area and Severity Index score, itch-numeric rating scale (NRS) score ≤ 1, sleep-NRS score ≤ 1 and Dermatology Life Quality Index ≤ 1] were investigated. Results In total, 2576 patients were enrolled from June 2018 to July 2022. MDA optimal treatment target criteria were achieved by 506/2309 (21.9%), 769/1959 (39.3%), 628/1247 (50.4%), 330/596 (55.4%) and 58/106 (54.7%) of those that reached 4, 12, 24, 36 and 48 months of follow-up, respectively. Logistic regression revealed a negative effect on MDA achievement for conjunctivitis and food allergy at all timepoints. Adverse events (AEs) were mild and were observed in 373/2364 (15.8%), 166/2066 (8.0%), 83/1291 (6.4%), 27/601 (4.5%) and 5/110 (4.5%) of those that reached 4, 12, 24, 36 and 48 months of follow-up. Conjunctivitis was the most frequently reported AE during the available follow-up. AEs led to treatment discontinuation in < 1% of patients during the evaluated time periods. Conclusions The high long-term effectiveness and safety of dupilumab were confirmed in this dynamic cohort of patients with moderate-to-severe AD, regardless of clinical phenotype and course (persisting or relapsing) at baseline. Further research will be needed to investigate the effect of T helper cell 2 comorbidities and disease duration on the response to dupilumab and other newer therapeutics for AD.

The beneficial effects of ethanolic extract of Sargassum serratifolium in DNCB-induced mouse model of atopic dermatitis

Atopic dermatitis is a chronic complex inflammatory skin disorder that requires sustainable treatment methods due to the limited efficacy of conventional therapies. Sargassum serratifolium, an algal species with diverse bioactive substances, is investigated in this study for its potential benefits as a therapeutic agent for atopic dermatitis. RNA sequencing of LPS-stimulated macrophages treated with ethanolic extract of Sargassum serratifolium (ESS) revealed its ability to inhibit a broad range of inflammation-related signaling, which was proven in RAW 264.7 and HaCaT cells. In DNCB-induced BALB/c or HR-1 mice, ESS treatment improved symptoms of atopic dermatitis within the skin, along with histological improvements such as reduced epidermal thickness and infiltration of mast cells. ESS showed a tendency to improve serum IgE levels and inflammation-related cytokine changes, while also improving the mRNA expression levels of Chi3l3, Ccr1, and Fcεr1a genes in the skin. Additionally, ESS compounds (sargachromanol (SCM), sargaquinoic acid (SQA), and sargahydroquinoic acid (SHQA)) mitigated inflammatory responses in LPS-treated RAW264.7 macrophages. In summary, ESS has an anti-inflammatory effect and improves atopic dermatitis, ESS may be applied as a therapeutics for atopic dermatitis.

A Mouse Model of MC903-Induced Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic, relapsing, and extremely pruritic inflammatory skin disease with a particular impact on children. AD pathogenesis is not yet fully understood, and there is no curative treatment for this disease. Therefore, several genetically or chemically-induced AD mouse models have been developed. These preclinical mouse models are an indispensable research tool for studying AD pathogenesis and evaluating the efficacy of new candidate AD therapeutics. A commonly used mouse model of AD has been developed using the topical application of a low-calcemic analog of vitamin D3, MC903, to induce AD-like inflammatory phenotypes that closely resemble human AD. Moreover, this model shows a minimal effect on systemic calcium metabolism that is observed in the vitamin D3-induced AD model. Thus, an expanding number of studies use the MC903-induced AD model to interrogate AD pathobiology in vivo and to test new candidate small molecule and monoclonal antibody therapies. This protocol describes in detail functional measurements including the measurement of skin thickness, which is a surrogate marker for ear skin inflammation, as well as itch assessment, histological evaluation to assess the structural changes associated with AD skin inflammation, and preparation of single-cell suspensions from ear skin and draining lymph nodes for the assessment of inflammatory leukocyte subset infiltration in these tissues using flow cytometry. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Topical application of MC903 induces AD-like skin inflammation Support Protocol 1: Measurement of ear skin thickness Support Protocol 2: Itch assessment Support Protocol 3: Dissection of ear skin and ear draining lymph nodes Support Protocol 4: Histological evaluation and quantification Support Protocol 5: Preparation of single-cell suspension from ear skin and draining lymph nodes for the assessment of inflammatory immune cell infiltration using flow cytometry.

The underrepresentation of older adults in clinical trials of Janus kinase inhibitors in the treatment of atopic dermatitis

To the Editor: Older adults can comprise up to 13% of patients with atopic dermatitis (AD).1 Therefore, clinical trials of AD therapeutics need to adequately include adults over the age of 65 years to ensure that they are treated with medications, the safety and efficacy of which have been explicitly evaluated in their age group. Unfortunately, older adults are often underrepresented in clinical trials across numerous diseases,2,3 including those of systemic AD therapies (azathioprine, methotrexate, and mycophenolate mofetil).

Treatment-resistant atopic dermatitis: novel therapeutics, digital tools, and precision medicine.

Atopic dermatitis (AD) is a prevalent condition impacting up to 25% of children and 8% of adults worldwide. An estimated 20% of those with AD comprise a subset of patients with treatment-resistant AD, for whom traditional therapeutics and management strategies are unsuccessful. Physical symptoms significantly impact quality of life for patients and caregivers. The condition is chronic and may persist throughout the lifespan with recurrent episodes. Novel AD therapeutics offer new opportunities to resolve symptoms of treatment-resistant more effectively AD. Recently developed pharmacological agents were developed with an appreciation of AD as a heterogeneous condition. New advances include topical, oral, and injectable therapeutics with novel mechanisms of action. In addition, advances in clinical practice, including the application of digital tools, can promote a personalized medicine approach. For example, teledermatology for chronic conditions such as AD have been embraced by clinicians and patients; communicating symptoms via photographs can augment patient symptom trackers and aid trigger identification. Digital tools can also be used to increase medication adherence and improve patient/caregiver engagement. Integrating the above is a personalized medicine approach. Advanced therapeutics with novel mechanisms of action, integrated with digital tools, and trends toward patient-centered medicine can assist this chronic, heterogeneous condition via precision medicine and better treat treatment-resistant AD.

Huangbai Liniment Ameliorates Skin Inflammation in Atopic Dermatitis

Atopic dermatitis (AD), also known as atopic eczema, is one of the most common skin diseases and is characterized by allergic skin inflammation, redness, and itchiness and is associated with a hyperactivated type 2 immune response. The leading causes of AD include an imbalance in the immune system, genetic predisposition, or environmental factors, making the development of effective pharmacotherapies complex. Steroids are widely used to treat AD; however, they provide limited efficacy in the long term and can lead to adverse effects. Thus, novel treatments that offer durable efficacy and fewer side effects are urgently needed. Here, we investigated the therapeutic potential of Huangbai Liniment (HB), a traditional Chinese medicine, using an experimental AD mouse model, following our clinical observations of AD patients. In both AD patient and the mouse disease model, HB significantly improved the disease condition. Specifically, patients who received HB treatment on local skin lesions (3–4 times/day) showed improved resolution of inflammation. Using the 1-Chloro-2,4-dinitrobenzene (DNCB)-induced AD model in BALB/c mice, we observed that HB profoundly alleviated severe skin inflammation and relieved the itching. The dermatopathological results showed markedly reversed skin inflammation with decreased epidermal thickness and overall cellularity. Correspondingly, HB treatment largely decreased the mRNA expression of proinflammatory cytokines, including IL-1β, TNF-α, IL-17, IL-4, and IL-13, associated with declined gene expression of IL-33, ST2, and GATA3, which are connected to the type 2 immune response. In addition, HB restored immune tolerance by promoting regulatory T (TREG) cells and inhibiting the generation of TH1, TH2, and TH17 cells in vitro and in the DNCB-induced AD mouse model. For the first time, we demonstrate that HB markedly mitigates skin inflammation in AD patients and the DNCB-induced AD mouse model by reinvigorating the T cell immune balance, shedding light on the future development and application of novel HB-based therapeutics for AD.

Mouse models of atopic dermatitis: a critical reappraisal.

Mouse models for atopic dermatitis (AD) are an indispensable preclinical research tool for testing new candidate AD therapeutics and for interrogating AD pathobiology in vivo. In this Viewpoint, we delineate why, unfortunately, none of the currently available so-called "AD" mouse models satisfactorily reflect the clinical complexity of human AD, but imitate more "allergic" or "irriant" contact dermatitis conditions. This limits the predictive value of AD models for clinical outcomes of new tested candidate AD therapeutics and the instructiveness of mouse models for human AD pathophysiology research. Here, we propose to initiate a rational debate on the minimal criteria that a mouse model should meet in order to be considered relevant for human AD. We suggest that valid AD models should at least meet the following criteria: (a) an AD-like epidermal barrier defect with reduced filaggrin expression along with hyperproliferation, hyperplasia; (b) increased epidermal expression of thymic stromal lymphopoietin (TSLP), periostin and/or chemokines such as TARC (CCL17); (c) a characteristic dermal immune cell infiltrate with overexpression of some key cytokines such as IL-4, IL-13, IL-31 and IL-33; (d) distinctive "neurodermatitis" features (sensory skin hyperinnervation, defective beta-adrenergic signalling, neurogenic skin inflammation and triggering or aggravation of AD-like skin lesions by perceived stress); and (e) response of experimentally induced skin lesions to standard AD therapy. Finally, we delineate why humanized AD mouse models (human skin xenotransplants on SCID mice) offer a particularly promising preclinical research alternative to the currently available "AD" mouse models.

Treatments for Childhood Atopic Dermatitis: an Update on Emerging Therapies.

Atopic dermatitis (AD) is generally considered a T helper type 2-dominated disease. Pediatric AD is usually less severe than adult AD, but it may present as moderate to severe lesions that are inadequately managed by current modalities including emollients/moisturizers, topical corticosteroids (TCSs), topical calcineurin inhibitors (TCIs), and even systemic immunosuppressants (such as cyclosporine, azathioprine, methotrexate, and mycophenolate mofetil). In addition, systemic immunosuppressants are often not recommended for childhood AD by the current guidelines due to their toxicities. Therefore, there is still an unmet need for a safe and effective long-term therapy for pediatric AD patients whose disease is inadequately controlled or who are intolerant to current treatments. The emerging therapeutics for AD focuses on intervening in the inflammatory pathway by targeting specific cytokines/chemokines or their receptors. Monoclonal antibodies against immunoglobulin E (IgE), interleukin (IL)-4 receptor subunit α, IL-5, IL-13, IL-31 receptor subunit α, IL-33, and thymic stromal lymphopoietin (TSLP) have been evaluated clinically for AD. Encouraging results have been reported for many of the biologics, of which the most exciting is dupilumab. Other emerging systemic therapies include small molecules such as baricitinib, abrocitinib, upadacitinib, and tradipitant. Several novel topical agents are under clinical investigation for the treatment of AD, including topical phosphodiesterase 4 (PDE4) inhibitors, Janus kinase (JAK) inhibitors, aryl hydrocarbon receptor (AhR) modulating agents, and transient receptor potential vanilloid subfamily member 1 (TRPV1) antagonists. Accompanied by thorough characterization of different phenotype and endotype subsets, the application of precision medicine could provide new prospects for the optimal treatment of AD.

Protein-coding variants contribute to the risk of atopic dermatitis and skin-specific gene expression

Fifteen percent of atopic dermatitis (AD) liability-scale heritability could be attributed to 31 susceptibility loci identified by using genome-wide association studies, with only 3 of them (IL13, IL-6 receptor [IL6R], and filaggrin [FLG]) resolved to protein-coding variants. We examined whether a significant portion of unexplained AD heritability is further explained by low-frequency and rare variants in the gene-coding sequence. We evaluated common, low-frequency, and rare protein-coding variants using exome chip and replication genotype data of 15,574 patients and 377,839 control subjects combined with whole-transcriptome data on lesional, nonlesional, and healthy skin samples of 27 patients and 38 control subjects. An additional 12.56% (SE, 0.74%) of AD heritability is explained by rare protein-coding variation. We identified docking protein 2 (DOK2) and CD200 receptor 1 (CD200R1) as novel genome-wide significant susceptibility genes. Rare coding variants associated with AD are further enriched in 5 genes (IL-4 receptor [IL4R], IL13, Janus kinase 1 [JAK1], JAK2, and tyrosine kinase 2 [TYK2]) of the IL13 pathway, all of which are targets for novel systemic AD therapeutics. Multiomics-based network and RNA sequencing analysis revealed DOK2 as a central hub interacting with, among others, CD200R1, IL6R, and signal transducer and activator of transcription 3 (STAT3). Multitissue gene expression profile analysis for 53 tissue types from the Genotype-Tissue Expression project showed that disease-associated protein-coding variants exert their greatest effect in skin tissues. Our discoveries highlight a major role of rare coding variants in AD acting independently of common variants. Further extensive functional studies are required to detect all potential causal variants and to specify the contribution of the novel susceptibility genes DOK2 and CD200R1 to overall disease susceptibility.

Ameliorative effect of chlorin e6-mediated photodynamic therapy on DNCB-induced atopic dermatitis-like skin lesions in mice

Backgrounds: Atopic dermatitis (AD) is a chronic, inflammatory, and relapsing skin disorder that occurs due to a Th1/Th2 cytokine imbalance and an elevation of immunoglobulin E (IgE) levels. We investigated whether chlorin e6 (Ce6)-mediated photodynamic therapy (PDT), which is commonly used for the clinical treatment of several cancers and non-neoplastic skin disorders, has a therapeutic effect on AD. Methods: β-hexosaminidase assay was performed in RBL-2H3 stimulated by DNP-BSA. Total IgE levels and serum cytokine levels were analyzed by ELISA assay. Eosinophils and mast cells were analyzed by hematoxylin- eosin stain and toluidine blue stain on ear of AD mouse model. Results: Ce6-mediated PDT significantly reduced the secretion of β-hexosaminidase in DNP-BSA-stimulated RBL-2H3 cells. In a DNCB-induced AD-like mouse model, serum IFN-γ was found to be elevated in conjunction with reduced IL-4 following Ce6-mediated PDT. The DNCB-induced serum IgE level was also reduced following Ce6-mediated PDT. In addition, DNCB-induced infiltration of eosinophils and mast cells was decreased by Ce6-mediated PDT in the mouse ear. Conclusion: Ce6-mediated PDT might be used as a potent therapeutics for AD via restoring Th1/Th2 balance and reducing over expressed immune cells.

Adipose-derived stem cells attenuate atopic dermatitis-like skin lesions in NC/Nga mice.

There is an unmet need in novel therapeutics for atopic dermatitis (AD). We examined the effects of autologous adipose-derived stem cells (ADSCs) on AD-like skin lesions induced by the application of 2,4-dinitrochlorobenzene (DNCB) in NC/Nga mice. Autologous ADSCs and ADSC-conditioned medium (ADSC-CM) were injected intralesionally three times. Clinical severity and histopathologic findings were compared in sham naïve control, saline-treated, ADSC-treated, ADSC-CM-treated and 2.5% cortisone lotion-applied animals. The severity index, skin thickness, mast cell number, as well as expression levels of thymic stromal lymphopoietin, CD45, chemoattractant receptor-homologous molecule, chemokine ligand 9 and chemokine ligand 20 were significantly lower in mice treated with ADSC, ADSC-CM, or 2.5% cortisone lotion. Tissue levels of interferon-γ as well as serum levels of interleukin-33 and immunoglobulin E levels were also decreased in those groups. We conclude that autologous ADSCs improved DNCB-induced AD-like skin lesions in NC/Nga mice by reducing inflammation associated with Th2 immune response and interferon-γ.

Atopic dermatitis in African American patients is TH2/TH22-skewed with TH1/TH17 attenuation

BackgroundAfrican Americans (AA) are disproportionately impacted by atopic dermatitis (AD), with increased prevalence and therapeutic challenges unique to this population. Molecular profiling data informing development of targeted therapeutics for AD are derived primarily from European American (EA) patients. These studies are absent in AA, hindering development of effective treatments for this population. ObjectiveWe sought to characterize the global molecular profile of AD in the skin of AA patients as compared with that of EA AD and healthy controls. MethodsWe performed RNA-Seq with reverse transcription polymerase chain reaction validation and immunohistochemistry studies in lesional and nonlesional skin of AA and EA AD patients vs healthy controls. ResultsAfrican American AD lesions were characterized by greater infiltration of dendritic cells (DCs) marked by the high-affinity immunoglobulin E (IgE) receptor (FcεR1+) compared with EA AD (P < .05). Both AD cohorts showed similarly robust up-regulation of Th2-related (CCL17/18/26) and Th22-related markers (interleukin [IL]-22, S100A8/9/12), but AA AD featured decreased expression of innate immune (tumor necrosis factor [TNF], IL-1β), Th1-related (interferon gamma [IFN-γ], MX1, IL-12RB1), and Th17-related markers (IL-23p19, IL-36G, CXCL1) vs EA AD (P < .05). The Th2 (IL-13) and Th22-related products (IL-22, S100A8/9/12) and serum IgE were significantly correlated with clinical severity (Scoring of Atopic Dermatitis [SCORAD]) in AA. Fillagrin (FLG) was exclusively down-regulated in EA AD, whereas loricrin (LOR) was down-regulated in both AD cohorts and negatively correlated with SCORAD in AA. ConclusionThe molecular phenotype of AA AD skin is characterized by attenuated Th1 and Th17 but similar Th2/Th22-skewing to EA AD. Our data encourages a personalized medicine approach accounting for phenotype-specific characteristics in future development of targeted therapeutics and clinical trial design for AD.

Nocturnal movements in children with atopic dermatitis have a timing pattern: A case-control study

Nocturnal movements in children with atopic dermatitis have a timing pattern: A case-control study

Are Biologics Efficacious in Atopic Dermatitis? A Systematic Review and Meta-Analysis.

Current systemic treatments for atopic dermatitis (AD) offer limited efficacy and are often restricted by safety concerns. Biologics may address the unmet need for improved AD therapeutics. The aim of this study was to evaluate the efficacy and safety of biologic agents in AD. A systematic review and meta-analysis of studies evaluating AD patients treated with biologics was performed. The primary outcome was the Eczema Area and Severity Index (EASI)-75 response, while secondary outcomes were SCOring Atopic Dermatitis (SCORAD)-75, EASI-50, SCORAD-50, Investigator Global Assessment 0/1 responses, change in responses from baseline, and adverse events. We included 13 randomized controlled trials (RCTs) and 10 observational studies evaluating nine biologics. High-quality evidence was available for dupilumab, nemolizumab and ustekinumab. Pooling five studies, at weeks 12-16 dupilumab 300mg every week to every 2weeks achieved EASI-75 responses of 55%, superior to placebo [relative risk (RR) 3.3, 95% confidence interval (CI) 2.9-3.6]. Nemolizumab had similar EASI-75 responses as placebo, but significantly improved pruritus. In online reports, lebrikizumab demonstrated superior EASI-50 responses versus placebo (RR 1.3, 95% CI 1.04-1.7), while tralokinumab had superior SCORAD-50 responses versus placebo, with borderline significance (RR 1.7, 95% CI 0.97-3.1). In two RCTs each, omalizumab and ustekinumab were comparable with placebo, while antithymic stromal lymphopoietin receptor, infliximab, and rituximab lacked adequate evidence of efficacy. All medications had a comparable safety profile to placebo. Lack of RCTs and the use of variable outcome measures limited conclusions. Dupilumab is currently the only biologic with robust evidence of efficacy in AD. Nemolizumab, lebrikizumab, and tralokinumab show promise but further data are needed. Longer follow-up and larger studies will establish their safety profile.

Aryl hydrocarbon receptor activation restores filaggrin expression via OVOL1 in atopic dermatitis

Filaggrin (FLG) mutation is a well-confirmed genetic aberration in atopic dermatitis (AD). Genome-wide association studies on AD have revealed other susceptibility genes, for example, Ovo-like 1 (OVOL1). Nonetheless, the relation between FLG and OVOL1 is unclear. Because aryl hydrocarbon receptor (AHR; a ligand-activated transcription factor), plays a role in FLG expression in keratinocytes, we hypothesized that AHR regulates FLG expression via OVOL1. To demonstrate this mechanism, we analyzed FLG expression in OVOL1-overexpressing or OVOL1-knockdown normal human epidermal keratinocytes (NHEKs). Furthermore, we tested whether AHR activation by 6-formylindolo(3,2-b)carbazole (FICZ), an endogenous AHR ligand, or Glyteer, clinically used soybean tar, upregulates FLG and OVOL1 expression in NHEKs. We found that (1) OVOL1 regulates FLG expression; (2) AHR activation upregulates OVOL1; and (3) AHR activation upregulates FLG via OVOL1. Moreover, nuclear translocation of OVOL1 was less pronounced in AD skin compared with normal skin. IL-4-treated NHEKs, an in vitro AD skin model, also showed inhibition of the OVOL1 nuclear translocation, which was restored by FICZ and Glyteer. Thus, targeting the AHR–OVOL1–FLG axis may provide new therapeutics for AD.

Systemic therapies in atopic dermatitis: The pipeline

Atopic dermatitis (AD), the most prevalent inflammatory skin disease, is characterized by robust T-cell activation. The disease has several subtypes, all having a common T helper type 2 (Th2)/Th22 polarization, but it also displays differential immune skewing, such as increased Th17/interleukin 23 skewing in the skin of intrinsic, Asian, and early pediatric AD patients. Current systemic treatments for moderate to severe AD are largely unsatisfactory, associated with significant adverse effects and low compliance. A large unmet need exists for better therapeutics for moderate to severe AD. The translational revolution, first transforming the psoriasis treatment paradigm, is now becoming applicable for AD, with multiple targeted drugs being investigated in trials. The new treatments often have increased tolerability and specificity and higher efficacy compared with conventional treatments. The clinical testing of these targeted drugs can also provide an opportunity to further elucidate AD pathogenesis by dissecting the contribution of specific cytokines to the disease phenotype. By reviewing developing therapeutics for AD according to their pathway-specific mechanisms, this contribution also outlines the complex molecular characteristics of AD.

Spirodela polyrhiza extract modulates the activation of atopic dermatitis-related ion channels, Orai1 and TRPV3, and inhibits mast cell degranulation

Context: Spirodela polyrhiza (L.) Schleid. (Lemnaceae), Spirodelae Herba (SH), has been known to relieve inflammation, urticaria and skin symptoms including pruritus, eczema and rash. Objective: The effects of SH extract on two calcium ion channels, Orai1 and TRPV3, and their potential as novel therapeutics for atopic dermatitis (AD) were investigated. The regulatory role of Orai1 on mast cell degranulation was evaluated. Materials and methods: The dried leaves of SH were extracted by 70% methanol. Effects of SH extract (100 μg/mL) in an HEK293T cell line overexpressing human Orai1 or TRPV3 were assessed. Ion channel modulation in transfected HEK293T cells was measured using a conventional whole-cell patch-clamp technique. IgE-antigen complex-stimulated mast cell degranulation was measured by β-hexosaminidase assay with morphological observation after treatment with 20, 50 and 100 μg/mL SH extract. Results: SH extract (100 μg/mL) significantly inhibited Orai1 activity (63.8 ± 0.97%) in Orai1-STIM1 co-overexpressed HEK293T cells. SH extract significantly increased TRPV3 activity (81.29 ± 0.05% at −100 mV) compared with the positive control 2-APB (100 μM), which induced full activation. SH extract inhibited degranulation in IgE-antigen complex-stimulated RBL-2H3 mast cells by decreasing β-hexosaminidase activity (3.14 ± 0.03, 2.56 ± 0.12 and 2.29 ± 0.08 mU/mg, respectively). Conclusion: Our results suggested that SH extract could treat abnormal skin barrier pathologies in AD through modulation of the activities of the calcium ion channels Orai1 and TRPV3 and inhibition of mast cell degranulation. This is the first report of an herbal effect on the modulation of ion channels associated with skin barrier disruption in AD pathogenesis.

Group 2 Innate Lymphoid Cells Express Functional NKp30 Receptor Inducing Type 2 Cytokine Production.

Group 2 innate lymphoid cells (ILC2) are important in effector functions for eliciting allergic inflammation, parasite defense, epithelial repair, and lipid homeostasis. ILC2 lack rearranged Ag-specific receptors, and although many soluble factors such as cytokines and lipid mediators can influence ILC2, direct interaction of these cells with the microenvironment and other cells has been less explored. Natural cytotoxicity receptors are expressed by subsets of group 1 ILC and group 3 ILC and thought to be important for their effector function, but they have not been shown to be expressed by ILC2. Therefore, we sought to investigate the expression and functional properties of the natural cytotoxicity receptor NKp30 on human ILC2. A subset of ex vivo and cultured ILC2 express NKp30 that upon interaction with its cognate activatory ligand B7-H6 induces rapid production of type 2 cytokines. This interaction can be blocked by NKp30 blocking Ab and an inhibitory ligand, galectin-3. Higher expression of B7-H6 was observed in lesional skin biopsies of patients with atopic dermatitis, and incubation of keratinocytes with proinflammatory and type 2 cytokines upregulated B7-H6, leading to increased ILC2 cytokine production. NKp30-B7-H6 interaction is a novel cell contact mechanism that mediates activation of ILC2 and identifies a potential target for the development of novel therapeutics for atopic dermatitis and other atopic diseases.