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Therapeutic effects of recombinant Salmonella typhimurium harboring CCL22 miRNA on atopic dermatitis-like skin in mice.

ABSTRACT: Th-2-biased immune responses are known to play a key role in the pathogenesis of atopic dermatitis. In particular, the macrophage-derived chemokine CCL22 is directly implicated in Th-2-associated skin inflammatory reactions, and its levels are significantly elevated in serum and are correlated with disease severity in atopic dermatitis. In this study, we tested the development of genetic therapeutic options to treat atopic dermatitis using bacteria expressing miRNA. We constructed a recombinant strain of Salmonella typhimurium expressing CCL22 miRNA (ST-miRCCL22) for the in vivo knockdown of CCL22. The CCL22 gene was downregulated with CCL22 miRNA in activated lymphocytes. In mice with a cutaneous disease similar to atopic dermatitis, interleukin-4 was inhibited and interferon-g was induced after treatments with ST-miRCCL22. Furthermore, CCL22 levels were suppressed in the atopic mice treated with ST-miRCCL22. These results suggest that ST-miRCCL22 may be an effective genetic agent for treating atopic dermatitis.

SUBMITTER: Yoon WS

PROVIDER: S-EPMC3047194 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Therapeutic effects of recombinant Salmonella typhimurium harboring CCL22 miRNA on atopic dermatitis-like skin in mice.

Yoon Won Suck WS Lee Seung Seok SS Chae Yang Seok YS Park Yong Keun YK

Experimental & molecular medicine 20110201 2

Th-2-biased immune responses are known to play a key role in the pathogenesis of atopic dermatitis. In particular, the macrophage-derived chemokine CCL22 is directly implicated in Th-2-associated skin inflammatory reactions, and its levels are significantly elevated in serum and are correlated with disease severity in atopic dermatitis. In this study, we tested the development of genetic therapeutic options to treat atopic dermatitis using bacteria expressing miRNA. We constructed a recombinant ...[more]

PMID: 21187702

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Project description:BACKGROUND:Atopic dermatitis (AD) is associated with itch, skin inflammation and barrier disruption, and scratching, all of which may be associated with skin pain. OBJECTIVE:To characterize the patient burden of skin pain in AD. METHODS:We performed a prospective dermatology practice-based study using questionnaires and evaluation by a dermatologist. RESULTS:Overall, 305 patients (age range, 13-97 years) were included in the study, with 564 encounters. The cohort included 195 females (63.9%) and 193 whites (63.7%). The mean (SD) age at enrollment was 42.3 (18.1) years, and the mean (SD) age of patient-reported AD onset was 29.6 (31.9) years. At baseline, 144 patients (42.7%) reported skin pain in the past week, with 42 (13.8%) reporting severe or very severe pain. Twenty-four (16.8%) thought the skin pain was part of their itch, 16 (11.2%) from scratching, and 77 (72.0%) from both. Patients with skin pain were more likely to describe their itch using terms that resembled neuropathic pain. Prevalence of skin pain was increased in patients with vs without excoriations (72.6% vs 57.6%; ?2 test P?=?.02) but not other morphologic characteristics. Skin pain severity was most strongly correlated with the Patient-Oriented Eczema Measure (Spearman ??=?0.54), followed by ItchyQOL (??=?0.52), 5-dimensions of itch scale (??=?0.47), Dermatology Life Quality Index (??=?0.45), numeric rating scale for itch (??=?0.43) and sleep (??=?0.36), Patient Health Questionnaire 9 (??=?0.36), patient-reported global AD severity (??=?0.34), Eczema Area and Severity Index (??=?0.23), and objective Scoring AD index (??=?0.20) (P?<?.001 for all). Patients with both severe itch and pain vs those with only one or neither symptom being severe had significant increases in all these measures. CONCLUSION:Skin pain is a common and burdensome symptom in AD. Skin pain severity should be assessed with itch severity in AD patients and may be an important end point for monitoring treatment response.

Project description: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.

Project description:BackgroundMonitoring the effects of biologic therapies in skin diseases will benefit from alternative noninvasive skin sampling techniques to evaluate immune pathways in diseased tissue early and longitudinally.ObjectiveTo establish a minimally invasive profiling of skin cytokines for diagnosis, therapeutic response monitoring, and clinical research in atopic dermatitis (AD) and other skin diseases, particularly in pediatric cohorts.MethodsWe developed a novel method for cytokine profiling in the epidermis using skin tape strips (STSs) in a setting designed to maximize the efficiency of protein extraction from STSs. This method was applied to analyze STS protein extracts from the lesional skin of children having AD (n = 41) and normal, healthy controls (n = 22). A total of 20 cytokines were probed with the ultrasensitive Mesoscale multiplex cytokine assay.ResultsA significant increase in interleukin (IL)-1b (P < .01), IL-18 (P < .001), and IL-8 (P < .001) with a decrease in IL-1a (P < .001) in the stratum corneum of AD lesional skin was found. Concurrently, an increase in markers associated with type 2 inflammatory response was readily detectable in AD lesional skin, including C-C motif chemokine ligand (CCL) 22, CCL 17, and thymic stromal lymphopoietin (TSLP). The levels of IL-1b, IL-18, and TSLP exhibited positive correlations with the AD severity index (Scoring AD index) and skin transepidermal water loss (TEWL), whereas an inverse correlation between IL-1a and Scoring AD index and IL-1a and TEWL was found. The levels of CCL17, CCL22, TSLP, IL-22, and IL-17a correlated with skin TEWL measurements.ConclusionUsing minimally invasive STS analysis, we identified cytokine profiles easily sampled in AD lesional skin. The expression of these markers correlated with disease severity and reflected changes in TEWL in lesional skin. These markers suggest new response assessment targets for AD skin.Trial registrationClinicalTrials.gov Identifier: NCT03168113.

Project description:BackgroundEczema vaccinatum (EV), a disseminated viral skin infection, is a life-threatening complication of vaccinia virus (VV) inoculation in patients with atopic dermatitis (AD) and is thought to be associated with a defective innate immune response. However, the precise mechanism or mechanisms and key factor or factors of EV are unknown.ObjectiveGiven that patients with psoriasis, another inflammatory skin disorder, are not susceptible to EV, we compared the global transcriptional response of skin to VV in healthy subjects, patients with psoriasis, and patients with AD, focusing on AD-specific genes. We hypothesized that differences in the transcriptional response to VV between patients with AD and patients with psoriasis or healthy subjects would identify a defective pathway or pathways that might be associated with the development of EV.MethodsGene expression profiling of sham-treated and VV-treated unaffected skin explants from patients with AD (n = 12), patients with psoriasis (n = 12), or healthy subjects (n = 13) were generated with U133_Plus2 (54,613 probe sets) GeneChips and analyzed with the GCOS_1.4/SAM_2.1/MAPPFinder_2.0 pipeline.ResultsSixty-seven genes were significantly affected by VV in AD skin but not in psoriatic and healthy skin. Genes associated with defense response, response to wounding, and immune response were the most affected by VV in AD skin. All genes in these ontologies were downregulated, including the innate immunity genes leukotriene B(4) receptor (LTB4R), orosomucoid 1 (ORM1), coagulation factor II (thrombin) receptor (F2R), complement component 9 (C9), and LPS-binding protein (LBP). These findings were confirmed by means of real-time PCR and validated by means of PubMatrix analysis. ORM1, Toll-like receptor 4 (TLR4), and NLR family pyrin domain containing 1 (NLRP1) genes were also linked to AD severity.ConclusionThis study identified groups of innate immunity genes that are associated with the aberrant response of AD skin to VV and represent potential targets for EV pathogenesis.

Dataset Information

Therapeutic effects of recombinant Salmonella typhimurium harboring CCL22 miRNA on atopic dermatitis-like skin in mice.

Publications

Therapeutic effects of recombinant Salmonella typhimurium harboring CCL22 miRNA on atopic dermatitis-like skin in mice.

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