AD-like Skin Inflammation Research Articles

Skin-infiltrating basophils promote atopic dermatitis-like inflammation via IL-4 production in mice.

Patients with atopic dermatitis (AD) often show the infiltration of basophils in the affected skin. Because basophils represent only a minor fraction among cellular infiltrates in the skin lesion, the functional significance of skin-infiltrating basophils in AD pathogenesis remains ill-defined. In this study, we aimed to clarify the role of basophils and their effector molecules triggering skin inflammation in oxazolone (OX)-induced murine model of AD. A panel of mouse strains were sensitized and repeatedly challenged with topical applications of OX to induce AD-like skin inflammation. Both local and systemic Th2 immune responses were analyzed. Basophils progressively accumulated in the skin lesion but barely in draining lymph nodes (LNs). When basophils were depleted during the elicitation phase, skin inflammation was ameliorated while Th2 cell differentiation in draining LNs remained intact. The expression of IL-4 was highly upregulated in the affected skin, and basophils turned out to be the major producers of IL-4 among cellular infiltrates, suggesting the involvement of basophil-derived IL-4 in the Th2 skin inflammation. Indeed, basophil-specific IL-4-deficient mice displayed attenuated skin inflammation with a marked reduction of IL-4 in the skin lesion, even though cutaneous basophil infiltration and serum levels of IgE remained intact. Skin-infiltrating basophils promoted OX-induced AD-like skin inflammation through their local production of IL-4, rather than the induction of Th2 cell differentiation in draining LNs. This study suggests that the selective targeting of basophils could be a beneficial strategy in the treatment of a certain type of AD.

O-Coumaric acid attenuates atopic dermatitis-like skin inflammation

Abstract Background Hydroxycinnamic acids (coumaric acid; CA) and their derivatives display anti-oxidant and anti-inflammatory effects. CA has three isomers including o-CA, m-CA, and p-CA. Among them, recent report showed the effectiveness of p-CA on skin inflammation. Objective In this study, we investigated the role of o-CA on atopic dermatitis (AD) comparing with p-CA. Methods For the induction of atopic dermatitis (AD)-like skin inflammation, 1,4-dinitrochlorobenzene (DNCB) and house dust mite extract (Dermatophagoides farinae extract, DFE) were applicated repeatedly, and o-CA were orally administered. For mechanism study, tumor necrosis factor (TNF)-α and interferon (IFN)-γ stimulated human keratinocyte cell line (HaCaT) was used. Results In AD-like skin inflammation, the clinical symptoms including the redness, dermal/epidermal thickness, and infiltration of mast cells were significantly reduced by the oral treatment of o-CA. Local inflammatory cytokines expression and systemic production of IgE and IgG2a were also suppressed by the o-CA. In addition, o-CA inhibited the expression of interleukin (IL)-1β, IL-6 and CC-chemokine ligand 17 in TNF-α/IFN-γ stimulated HaCaT cells by the reduction of nuclear translocation of nuclear factor-κB. In all cases, o-CA showed more effectiveness than p-CA. Conclusions These results showed that o-CA could be a potential candidate for AD treatment.

Anti-Inflammatory Effect of Mallotus Philippinensis Bark Extracts in a Mouse Atopic Dermatitis Model

Background: Atopic Dermatitis (AD) is a chronic inflammatory skin disease that causes functional disruption of the skin barrier. We previously found that ethanol Extracts of Mallotus Philippinensis Bark (EMPB) promoted migration of mesenchymal stem cells and improved wound healing probably through anti-inflammatory action. However, direct evidence of the anti-inflammatory effect of EMPB and the underlying mechanisms of this action remain unknown. In the present study, we evaluated whether EMPB has an effective action on anti-inflammation using an in vitro and in vivo model. We found that topical application of EMPB improved house dust miteinduced AD-like skin inflammation in NC/Nga mice. In addition, EMPB significantly inhibited various kinds of inflammatory mediators such as interleukin-1ß, inducible nitric oxide synthases, and nuclear factorkappa B in lipopolysaccharide-stimulated macrophage cells. Moreover, EMPB exhibited marked radical scavenging ability. Taken together, these results suggest that EMPB may be useful in the treatment of skin inflammatory diseases such as AD. Keywords: Mallotus Philippinensis Bark; Anti-Inflammation; Atopic Dermatitis; Macrophages

Lack of interleukin-33 and its receptor does not prevent calcipotriol-induced atopic dermatitis-like inflammation in mice

Current studies addressing the influence of interleukin-33 or its receptor (IL-33R/ST2) on development of atopic dermatitis-like inflammation in mice have reported conflicting results. We compared the response in single- and double-deficient IL-33−/−/ST2−/− C57BL/6J BomTac mice in the well-established calcipotriol-induced model of atopic dermatitis. All genotypes (groups of up to 14 mice) developed atopic dermatitis-like inflammation yet we observed no biologically relevant difference between groups in gross anatomy or ear thickness. Moreover, histological examination of skin revealed no differences in mononuclear leukocyte and granulocyte infiltration nor Th2 cytokine levels (IL-4 and IL-13). Finally, skin CD45+ cells and CD3+ cells were found at similar densities across all groups. Our findings indicate that lack of interleukin-33 and its receptor ST2 does not prevent the development of AD-like skin inflammation.

Non-thermal plasma inhibits mast cell activation and ameliorates allergic skin inflammatory diseases in NC/Nga mice

Non-thermal plasma (NTP) has many functional activities such as, sterilization, wound healing and anti-cancer activity. Despite of its wide spread biomedical application, the effect of NTP on immune cells and allergic response has not been well studied. In this study, we determined whether NTP suppresses mast cell activation, which is important for allergic response, and ameliorates an atopic dermatitis (AD)-like skin inflammatory disease in mice. Exposure to NTP-treated medium during mast cell activation inhibited the expression and production of IL-6, TNF-α and suppressed NF-κB activation. We also investigated whether NTP treatment ameliorates house dust mite (HDM)-induced AD-like skin inflammation in mice. NTP treatment inhibited increases in epidermal thickness and recruitment of mast cells and eosinophils, which are important cell types in AD pathogenesis. In addition, Th2 cell differentiation was induced by application of HDM and the differentiation was also inhibited in the draining lymph node of NTP-treated mice. Finally, the expression of AD-related cytokines and chemokines was also decreased in NTP-treated mice. Taken together, these results suggest that NTP might be useful in the treatment of allergic skin diseases, such as AD.

392 Ruxolitinib cream ameliorates spontaneous atopic dermatitis in the IL-33 transgenic mouse model

Atopic dermatitis (AD) is characterized by intense itch and recurrent eczematous lesions. Interleukin (IL)-33 is constitutively produced from the structural and lining cells, including skin epithelial cells, which are exposed to the environment. Extracellular IL-33 binds to ST2 on T helper 2 (Th2) cells and various innate immune cells including mast cells, eosinophils and innate lymphoid cells. In AD patients, IL-33 overexpression in the epidermis, infiltration of ST2-positive cells and elevated serum IL-33 levels has been implicated in disease pathogenesis. Transgenic mice with constitutive epidermal-specific IL-33 expression (IL-33tg) spontaneously develop a progressive, AD-like skin inflammation and pruritis. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is involved in AD-related cytokine signaling, including IL-33, mediating downstream inflammation and barrier alterations. Ruxolitinib cream, a topical JAK1/2 inhibitor, is currently being evaluated in clinical trials for the treatment of mild-to-moderate AD (NCT03745638 & NCT03538041 and NCT03745651). Our goal was to evaluate Ruxolitinib cream as a monotherapy for the treatment of pruritis in the spontaneous onset IL-33 transgenic mouse model of AD. Animals were randomized to four treatment groups; vehicle cream (bid), ruxolitinib cream 1.5% (bid), topical steroid (clobetasol 0.05%) and vehicle treated (bid) non-transgenic littermates. Scratching and grooming analysis was performed at 14 and 24 weeks of age. Skin inflammation and mast cell frequency were quantified by histology. Tissue biopsies were analyzed for JAK-STAT pathway modulation and disease pathogenesis markers. Ruxolitinib cream treatment (1.5% bid) demonstrated sustained amelioration of pruritus (p<0.05) and abnormal grooming behaviors (p<0.001) at 14 and 24 weeks of age. Chronic topical administration of ruxolitinib cream was well tolerated in the IL-33tg mice. Together, these data support the scientific rationale that ruxolitinib cream, a topical JAK1/2 inhibitor, may have potential as a therapeutic agent for the treatment of atopic dermatitis.

Prostaglandin E2 (PGE2)–EP2 signaling negatively regulates murine atopic dermatitis–like skin inflammation by suppressing thymic stromal lymphopoietin expression

Atopic dermatitis (AD) is a common and chronic inflammatory skin disease of type 2 immunity. Keratinocyte-derived cytokines, including thymic stromal lymphopoietin (TSLP) and IL-33, are considered to induce the development of AD. Production of prostanoids, a family of lipid mediators, is increased in AD lesions. However, their physiologic functions remain to be clarified. We sought to elucidate the functions of prostanoids in the development of AD. The roles of prostanoids were investigated in a mouse model of AD induced by repeated application of hapten and PAM212, a keratinocyte cell line. Application of indomethacin, which blocks prostanoid synthesis, leads to enhanced TSLP and IL-33 production in the skin, increased serum IgE levels, and exacerbation of skin inflammation in this AD model. The skin inflammation was attenuated in TSLP receptor-deficient mice but not in IL-33-deficient mice, and the indomethacin-enhanced type 2 immune responses were abolished in TSLP receptor-deficient mice. Indomethacin increased protease-activated receptor 2-mediated TSLP production in keratinocytes invitro, and prostaglandin E2 reversed the increase in TSLP levels through its receptor, the prostaglandin E2 receptor (EP2), by downregulating surface expression of protease-activated receptor 2. Administration of an EP2 agonist canceled indomethacin-enhanced TSLP production and type 2 immune responses in the skin, whereas an EP2 antagonist caused an enhancement of TSLP production and type 2 immune responses in the skin. Prostaglandin E2-EP2 signaling negatively regulates murine AD-like skin inflammation by suppressing TSLP expression.

Soshiho-Tang, a Traditional Herbal Medicine, Alleviates Atopic Dermatitis Symptoms via Regulation of Inflammatory Mediators.

Soshiho-tang (SST) is a well-known traditional herbal medicine used for the treatment of many diseases. The aims of this study are to investigate the effects of SST on atopic dermatitis (AD) symptoms and to examine its mechanism. Human keratinocyte (HaCaT) cells were stimulated with tumor necrosis factor alpha (TNF-α)/IFN-γ to induce AD-like keratinocyte environment. 2,4-Dinitrochlorobenzene (DNCB) was used to induce AD-like skin lesions in the dorsal skin of BALB/c mice. SST and dexamethasone were administered orally for 14 day. As a result, SST treatment increased the expression of heme oxygenase-1 (HO-1), an anti-oxidative factor, and the nuclear translocation of NF-E2 p45-related factor 2 (Nrf2). In addition, the treatment also decreased the expression level of inflammatory mediator nuclear factor-κB (NF-κB) and the adhesion molecule intercellular adhesion molecule-1 (ICAM-1). SST treatment (75 and 150 mg/kg) significantly relieved AD symptoms in DNCB-induced AD-like mice by restoring skin thickness, spleen weight, immunoglobulin E (IgE), interleukin 4 (IL-4), pro-inflammatory cytokine expression, and expression of several other mediators. We found that SST alleviates AD-like skin lesions and skin inflammation by modulating various atopic symptoms and inflammatory mediators. Therefore, SST can be used as an alternative drug for the treatment of AD.

505 Therapeutic activity of an anti-IL36R blocking antibody in inhibiting atopic dermatitis-like skin inflammation in mice

Staphylococcus aureus epicutaneous exposure to mouse skin was previously found to induce atopic dermatitis (AD)-like inflammation that was dependent upon IL-36 receptor (IL-36R) activity. However, whether systemic treatment with an anti-IL-36R blocking monoclonal antibody (mAb) could have a therapeutic effect by diminishing IL-36-dependent S. aureus-induced skin inflammation is unclear. Herein, we evaluated the efficacy of an IL-36R blocking mAb in inhibiting AD-like inflammation induced by S. aureus epicutaneous exposure to mouse skin. S. aureus epicutaneous exposure was performed by applying a S. aureus (1 x 108 CFU) soaked gauze pad for 7 days on dorsal skin while the mice were treated with systemic administration (intraperitoneal) of an anti-IL-36R blocking mAb or isotype control mAb on days -1, 2 and 5. The anti-IL-36R blocking mAb treatment resulted in significantly decreased AD-like skin inflammation as measured by disease score (edema, erythema, necrosis and scaling) by a blinded evaluator, epidermal thickness quantified from histologic sections, and decreased neutrophil recruitment but not total or IL-17-producing T cell (CD3+, γδ, CD4+ and CD8+ T cell subsets) recruitment to the skin as measured by flow cytometry compared with isotype control-treated mice. Taken together, anti-IL-36R blocking mAb treatment inhibited AD-like skin inflammation induced by S. aureus epicutaneous exposure in a mechanism associated with decreased neutrophil but not T cell recruitment to the affected skin.

Inhibitory effect of ethanol extract of Ampelopsis brevipedunculata rhizomes on atopic dermatitis-like skin inflammation

Ethnopharmacological relevanceExtracts from various parts of Ampelopsis brevipedunculata has been used as anti-inflammatory agents in Asian folk medicine.Aim of the study: To demonstrate the medicinal effect of the A. brevipedunculata in skin inflammation, specifically atopic dermatitis (AD). Materials and methodsThe effect of ethanol extract of A. brevipedunculata rhizomes (ABE) on AD was examined using an AD-like skin inflammation model induced by repeated exposure to house dust mite (Dermatophagoides farinae extract, DFE) and 2,4-dinitrochlorobenzene (DNCB). The mechanism study was performed using tumor necrosis factor (TNF)-α and interferon (IFN)-γ-activated human keratinocytes (HaCaT). Serum histamine and immunoglobulin levels were quantified using enzymatic kits, while the gene expression of cytokines and chemokines was analyzed using quantitative real time polymerase chain reaction. The expression of signaling molecules was detected using Western blot. ResultsOral administration of ABE alleviated DFE/DNCB-induced ear thickening and clinical symptoms, as well as immune cell infiltration (mast cells and eosinophils) into the dermal layer. Serum Immunoglobulin (Ig) E, DFE-specific IgE, IgG2a, and histamine levels were decreased after the administration of ABE. ABE also inhibited CD4+IFN-γ+ and CD4+IL-4+ lymphocyte polarization in lymph nodes and expression of TNF-α, IFN-γ, IL-4, IL-13, and IL-31 in the ear tissue. In TNF-α/INF-γ-stimulated keratinocytes, ABE inhibited the gene expression of TNF-α, IL-6, IL-1β, and CCL17. In addition, ABE decreased the nuclear localization of signal transducer and activator of transcription 1 and nuclear factor-κB, and the phosphorylation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. ConclusionCollectively, our data demonstrate the pharmacological role and signaling mechanism of ABE in the regulation of skin allergic inflammation, which supports our suggestion that ABE could be developed as a potential therapeutic agent for the treatment of AD.

Ets1 suppresses atopic dermatitis by suppressing pathogenic T cell responses.

Atopic dermatitis (AD) is a complex inflammatory skin disease mediated by immune cells of both adaptive and innate types. Among them, CD4+ Th cells are one of major players of AD pathogenesis. Although the pathogenic role of Th2 cells has been well characterized, Th17/Th22 cells are also implicated in the pathogenesis of AD. However, the molecular mechanisms underlying pathogenic immune responses in AD remain unclear. We sought to investigate how the defect in the AD susceptibility gene, Ets1, is involved in AD pathogenesis in human and mice and its clinical relevance in disease severity by identifying Ets1 target genes and binding partners. Consistent with the decrease in ETS1 levels in severe AD patients and the experimental AD-like skin inflammation model, T cell-specific Ets1-deficient mice (Ets1ΔdLck) developed severe AD-like symptoms with increased pathogenic Th cell responses. A T cell-intrinsic increase of gp130 expression upon Ets1 deficiency promotes the gp130-mediated IL-6 signaling pathway, thereby leading to the development of severe AD-like symptoms. Functional blocking of gp130 by selective inhibitor SC144 ameliorated the disease pathogenesis by reducing pathogenic Th cell responses. Our results reveal a protective role of Ets1 in restricting pathogenic Th cell responses and suggest a potential therapeutic target for AD treatment.

Enhanced therapeutic effects of human mesenchymal stem cells transduced with superoxide dismutase 3 in a murine atopic dermatitis-like skin inflammation model.

The use of mesenchymal stem cells (MSCs) has been proposed to treat various autoimmune diseases. However, effective strategies for treating atopic dermatitis (AD) are still lacking, and the mechanisms underlying stem cell therapy remain largely unknown. In this study, we sought to explore potential clinical application of superoxide dismutase 3-transduced MSCs (SOD3-MSCs) to experimental AD-like skin inflammation in invitro and invivo and its underlying anti-inflammatory mechanisms. SOD3-MSCs were administered subcutaneously to mice with AD, and associated symptoms and biologic changes were evaluated. Human keratinocytes, mast cells, and murine T helper (Th) 2 cells were cocultured invitro with SOD3-MSCs to investigate potential therapeutic effects of SOD3-MSCs. In mice with AD, SOD3-MSCs ameliorated AD pathology and enhanced the efficacy of MSC therapy by controlling activated immune cells, by reducing expression levels of proinflammatory mediators in the skin, and by inhibiting the histamine H4 receptor (H4R)-mediated inflammatory cascade and activation of Janus kinase signal transducer and activator of transcription pathways. Similarly, coculture of SOD3-MSCs with mast cells, keratinocytes, and Th2 cells effectively dampened H4R-dependent persistent inflammatory responses by multiple mechanisms. Moreover, we also showed that SOD3 interacts with H4R and IL-4 receptor α. The functional significance of this interaction could be a markedly reduced inflammatory response in keratinocytes and overall AD pathogenesis, representing a novel mechanism for SOD3's anti-inflammatory effects. SOD3-MSCs can be potentially used as an effective and clinically relevant therapy for AD and other autoimmune disorders.

113 Epicutaneous allergen exposure induces pathogenic IL-22-producing T helper cells

Atopic dermatitis (AD) is a common inflammatory skin disease resulting from epidermal barrier dysfunction and an immune response dominated by IL-4-producing Th2 cells and IL-22-producing Th22 cells. Environmental antigens like food allergens are thought to influence the clinical course of AD. We aimed to study the pathogenic phenotype of food allergen-specific T cells activated through the skin or by oral exposure and their potency to transfer skin inflammation. Ovalbumin (OVA) TCR-transgenic mice were sensitized epicutaneously with OVA or were fed OVA. CD4+ T cells from skin or mesenteric lymph nodes were phenotyped for cytokine expression and transferred into naïve BALB/c mice. Recipient mice were challenged with OVA epicutaneously. Skin inflammation was determined histologically. T cells activated through epicutaneous or oral OVA exposure in donor mice both migrate to skin lymph nodes after adoptive transfer and epicutaenous OVA exposure of recipient mice. Importantly, AD-like skin inflammation could only be induced by the transfer of epicutaneously primed OVA T cells. Analysis of the immune phenotype demonstrated an IL-22/IL-17A-dominated immune phenotype of skin-pathogenic T cells. IL-22 seems to be the critical cytokine for the development of AD and is induced in this model by epicutaneous sensitization with OVA.

The suppressive effect of puerarin on atopic dermatitis-like skin lesions through regulation of inflammatory mediators in vitro and in vivo

Atopic dermatitis (AD) is one of the common inflammatory immune disorders. Puerarin is the main isoflavonoid obtained from the root of Pueraria lobata and has been known have ameliorative effects on diverse inflammatory diseases. However, the effects of puerarin on AD have not been uncovered. 2,4-dinitrochlorobenzene (DNCB) was used to induce atopic dermatitis(AD)-like skin lesions on BALB/c mice for 17 days. Further, the BALB/c mice were orally administered puerarin. Puerarin ameliorated DNCB-induced AD-like symptoms in the mice by regulating skin thickness, degranulation of mast cells, and serum immunoglobulin E (IgE). Human keratinocytes (HaCaT cells) were also used to clarify the effects of puerarin on the secretion of pro-inflammatory cytokines. Puerarin inhibited the secretion of inflammatory cytokines and chemokines. The aim of this study was to investigate the protective and alleviative effect of puerarin on AD in vitro and in vivo. The results in this study indicated that puerarin ameliorates AD-like skin lesion and skin inflammation via regulation of various atopic and inflammatory mediators. Therefore, puerarin might be useful in treating AD and other skin diseases.

Neutralization of IL-17C Reduces Skin Inflammation in Mouse Models of Psoriasis and Atopic Dermatitis

IL-17C is a functionally distinct member of the IL-17 family that was believed to play a role in the pathogenesis of psoriasis. Here we confirmed that IL-17C is involved in psoriasis and explored potential roles for IL-17C in atopic dermatitis (AD). An anti-IL-17C antibody, MOR106, was generated that potently and selectively binds to human and mouse IL-17C, thereby inhibiting the binding of IL-17C to its IL-17RE receptor. The antibody inhibited cutaneous inflammation in an IL-23-induced psoriatic-like skin inflammation model. In lesional skin of patients with AD, IL-17C expression levels were increased and localized to keratinocytes and infiltrating immune cells. To determine the contribution of IL-17C to AD pathogenesis, MOR106 was tested in two distinct invivo models. In the calcipotriol-induced AD model, ear skin inflammation, TSLP, and IL-33 protein production in ears was suppressed by MOR106. Consistently, in the flaky tail strain mouse model, spontaneous development of AD-like skin inflammation was reduced by MOR106. Moreover, serum IgE levels, number of mast cells in skin and T helper type 2-related cytokines IL-4 and CCL17 in serum were all reduced. Overall, our resultsindicate that IL-17C is a central mediator of skin inflammation beyond psoriasis and is relevant in particular in AD.

Role of mast cells in Staphylococcus aureus enterotoxin Binduced atopic dermatitis-like skin inflammation in mice

Objective To investigate the role of mast cells in Staphylococcus aureus enterotoxin B (SEB) -induced atopic dermatitis (AD) -like skin inflammation in BALB/c mice. Methods A total of 24 BALB/c mice were randomly and equally divided into 4 groups to be topically treated with ovalbumin (OVA group) , SEB (SEB group) , OVA+ SEB (OVA+ SEB group) and sodium chloride physiological solution (control group) respectively, so as to establish mouse models of epicutaneously induced AD-like skin inflammation. The AD-like skin lesions were evaluated by clinical observation and eczema area and severity index (EASI) . Biopsy specimens were obtained from lesional skin of mice and then subjected to toluidine blue staining and immunohistochemical staining to count the mast cells, observe the morphology and distribution of mast cells, and calculate the percentage of degranulated mast cells. Results After 7-week treatment, the OVA group, SEB group and OVA+ SEB group all showed severer local skin inflammation, higher EASI scores and denser infiltration of inflammatory cells compared with the control group. Moreover, the OVA+ SEB group showed significantly severer local skin inflammation, skin lesions and degree of infiltration of inflammatory cells compared with the OVA group and SEB group (all P < 0.05) . The number of mast cells in the dermis of AD-like skin lesions per high-power field (× 400) was significantly higher in the OVA group (median[quartile range]: 10.625[3.675]) , SEB group (11.000[4.163]) and OVA+ SEB group (13.875[8.813]) than that in the control group (5.925[2.088], all P < 0.05) . The SEB group (71.083% ± 14.519%) and OVA+ SEB group (58.767% ± 16.978%) both showed significantly higher percentage of degranulated mast cells compared with the OVA group (24.050% ± 11.161%, both P < 0.05) and control group (23.617% ± 8.132%, both P < 0.05) . Bivariate correlation analysis showed that the number of mast cells in the skin lesions was positively linearly correlated with the EASI scores (P < 0.05) . Conclusions Epicutaneous application of SEB can induce AD-like skin lesions in mice, and can exacerbate the severity of OVA-induced AD-like skin lesions. Mast cell proliferation, activation/degranulation and tryptase release may participate in the inflammation. Key words: Dermatitis, atopic; Mast cells; Staphylococcus aureus; Enterotoxins; Tryptases; Ovalbumin

374 Epicutaneous allergen exposure induces pathogenic IL-22-producing T helper cells

Atopic dermatitis (AD) is a common inflammatory skin disease resulting from epidermal barrier dysfunction and an immune response dominated by IL-4-producing Th2 cells and IL-22-producing Th22 cells. Environmental antigens like food allergens are thought to influence the clinical course of AD. We aimed to study the pathogenic phenotype of food allergen-specific T cells activated through the skin or by oral exposure and their potency to transfer skin inflammation. Ovalbumin (OVA) TCR-transgenic mice were sensitized epicutaneously with OVA or were fed OVA. CD4+ T cells from skin or mesenteric lymph nodes were phenotyped for cytokine expression and transferred into naïve BALB/c mice. Recipient mice were challenged with OVA epicutaneously. Skin inflammation was determined histologically. T cells activated through epicutaneous or oral OVA exposure in donor mice both migrate to skin lymph nodes after adoptive transfer and epicutaenous OVA exposure of recipient mice. Importantly, AD-like skin inflammation could only be induced by the transfer of epicutaneously primed OVA T cells. Analysis of the immune phenotype demonstrated an IL-22/IL-17A-dominated immune phenotype of skin-pathogenic T cells. IL-22 seems to be the critical cytokine for the development of AD and is induced in this model by epicutaneous sensitization with OVA.

Induction of skin-pathogenic Th22 cells by epicutaneous allergen exposure

BackgroundAtopic dermatitis (AD) is a common inflammatory skin disease with dysfunction of the skin barrier, an abnormal immune response and frequent allergies to environmental antigens like food antigens. Clinical observations suggest that certain diets can influence the course of AD. ObjectiveHere we compared the phenotype of food allergen-specific T cells activated through skin or gut allergen exposure to transfer skin inflammation into naïve recipients upon epicutaenous allergen challenge. MethodsOvalbumin (OVA) TCR-transgenic mice were treated epicutaneously with OVA or were fed OVA. CD4+ T cells from skin lymph nodes or mesenteric lymph nodes were transferred into naïve BALB/c mice, which were challenged with OVA epicutaneously. Skin inflammation was determined by histological parameters. In addition, we analyzed the phenotype of the immune response in lymphoid tissues and in skin tissue. ResultsTCR-transgenic T cells activated through epicutaneous or oral OVA exposure both migrate to skin lymph nodes after adoptive transfer and epicutaenous OVA exposure. AD-like skin inflammation could only be induced by the transfer of epicutaneously primed OVA T cells. Analysis of the immune phenotype demonstrated an IL-22/IL-17A-dominated immune phenotype of skin-pathogenic T cells. ConclusionIL-22 seems to be the critical cytokine for the development of AD and is induced in this model by epicutaneous sensitization with OVA.

Oral administration of lactobacilli isolated from Jeotgal, a salted fermented seafood, inhibits the development of 2,4-dinitrofluorobenzene-induced atopic dermatitis in mice.

Certain strains of lactobacilli have been reported to exert favorable effects on atopic dermatitis (AD). Jeotgal, a traditional Korean food, is a salted fermented seafood known to harbor many lactic acid bacteria. In the present study, two novel lactobacillus strains were isolated from Jeotgal, and their anti-AD effects were investigated. Lactobacilli isolated from Jeotgal were identified, according to conjugated linoleic acid-producing activity, as Lactobacillus plantarum (JBCC105645 and JBCC105683). AD-like skin lesions were induced in BALB/c mice using dinitrofluorobenzene (DNFB). Ear swelling, histological analysis and serum immunoglobulin E (IgE) levels in mice were evaluated to investigate the anti-AD effects of lactobacilli. Cytokine production of ex vivo cluster of differentiation (CD)4+ T cells, and interleukin (IL)-12 production of in vitro macrophages were also evaluated to establish a putative mechanism of the action of lactobacilli. Administration of JBCC105645 or JBCC105683 suppressed ear swelling and serum IgE levels in DNFB-treated mice (P<0.05). Notably, JBCC105645 was more effective than JBCC105683 (P<0.05). Treatment with the lactobacilli also induced a significant decrease in IL-4 production with concomitant increase in interferon (IFN)-γ production in DNFB-exposed CD4+ T cells, and an increase in IL-12 production in macrophages (P<0.05). Taken together, the lactobacilli isolated from Jeotgal may suppress the development of AD-like skin inflammation in mice by modulating IL-4 and IFN-γ production in CD4+ T cells, presumably via enhancing IL-12 production by macrophages.

Therapeutic effects of erythroid differentiation regulator 1 (Erdr1) on atopic dermatitis-like skin inflammation in NC/Nga mice

Abstract Atopic Dermatitis (AD) is a representative chronic inflammatory skin disease. It is characterized by a defective skin barrier and dysregulation of the immune system as result of excessive Th2 immune response. IL-18, a well-known pro-inflammatory cytokine, is particularly closely associated with AD severity and IgE level in AD patients. Recent studies have been reported that erythroid differentiation regulator (Erdr1) has a negative correlation with IL-18 and exerts anti-inflammatory effects on inflammatory skin diseases, such as psoriasis, rosacea, and melanoma. In this study, to investigate whether Erdr1 has a preventive effect on AD, NC/Nga mice were used to induce AD-like skin inflammation. Then, recombinant Erdr1 (rErdr1) was administered by intraperitoneal (i.p.) injection. As results, rErdr1 administration significantly decreased the severity of AD including redness, edema, scaling, and excoriation. In addition, IgE and IL-4 production were suppressed by rErdr1 in the AD mouse model. To elucidate the related mechanisms, the expression of Th2 chemoattractants and angiogenic factor was determined. The expression of CCL17 and CCL22 was significantly lower in rErdr1-treated mice than in vehicle control-treated mice. Also, a representative angiogenic factor, VEGF expression was inhibited by rErdr1 administration. To our knowledge, this is the first evidence that rErdr1 has a preventive effect on AD based on its ability to reduce Th2 chemoattractants and angiogenesis in an AD-like mouse model. Therefore, we suggest that supplementation with rErdr1 might be an effective and improved therapeutic strategy for the treatment of AD.