Atopic Inflammation Research Articles

902 Ablation of basophils reduces ILC2-dependent atopic dermatitis-like inflammation in mice overexpressing interleukin-33 in the skin

902 Ablation of basophils reduces ILC2-dependent atopic dermatitis-like inflammation in mice overexpressing interleukin-33 in the skin

913 Caspase-1 regulates IL-33 secretion and partly mediates the development of atopic dermatitis-like inflammation in mice overexpressing IL-33 in the skin

913 Caspase-1 regulates IL-33 secretion and partly mediates the development of atopic dermatitis-like inflammation in mice overexpressing IL-33 in the skin

Esculetin from Fraxinus rhynchophylla attenuates atopic skin inflammation by inhibiting the expression of inflammatory cytokines

Atopic dermatitis (AD) is a common chronic inflammatory skin disorder afflicting from infancy to adults with itching, scratching, and lichenification. We aimed to investigate the effects of esculetin from Fraxinus rhynchophylla on atopic skin inflammation. For induction of atopic skin inflammation, we exposed the ears of female BALB/c mice to house dust mite (Dermatophagoides farinae extract, DFE) and 2,4-dinitrochlorobenzene (DNCB) for 4 weeks. Oral administration of esculetin reduced the symptoms of DFE/DNCB-induced atopic skin inflammation, which were evaluated based on ear swelling and number of scratch bouts. The immunoglobulin (Ig) E, IgG2a, and histamine levels in serum were decreased and inflammatory cell infiltration in skin tissue was reduced by the esculetin. It suppressed production of Th1, Th2 and Th17-related cytokines such as tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-4, IL-13, IL-31 and IL-17 in the ear tissue. Furthermore, we investigated the effects of esculetin on activated keratinocytes, which are representative cells used for studying the pathogenesis of acute and chronic atopic skin inflammation. As results, esculetin suppressed gene expression of Th1, Th2 and Th17 cytokines and the activation of nuclear factor-κB and signal transducer and activator of transcription 1 in TNF-α/IFN-γ-stimulated keratinocytes. Taken together, these results imply that esculetin attenuated atopic skin inflammation, suggesting that esculetin could be a potential therapeutic candidate for the treatment of AD.

Bee Venom Phospholipase A2 Alleviate House Dust Mite-Induced Atopic Dermatitis-Like Skin Lesions by the CD206 Mannose Receptor.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by highly pruritic, erythematous, and eczematous skin plaques. We previously reported that phospholipase A2 (PLA2) derived from bee venom alleviates AD-like skin lesions induced by 2,4-dinitrochlorobenzene (DNCB) and house dust mite extract (Dermatophagoides farinae extract, DFE) in a murine model. However, the underlying mechanisms of PLA2 action in actopic dermatitis remain unclear. In this study, we showed that PLA2 treatment inhibited epidermal thickness, serum immunoglobulin E (IgE) and cytokine levels, macrophage and mast cell infiltration in the ear of an AD model induced by DFE and DNCB. In contrast, these effects were abrogated in CD206 mannose receptor-deficient mice exposed to DFE and DNCB in the ear. These data suggest that bvPLA2 alleviates atopic skin inflammation via interaction with CD206.

Phenotypic and functional profile of Th17 and Treg cells in allergic fungal sinusitis

Interleukin-17 producing T helper (Th17) and regulatory T cells (Treg) cells have been identified to play a critical role in atopic inflammation. However, conflicting reports on the role of Th17/Treg cells in allergic fungal rhinosinusitis (AFRS) patients of different ethnicities has mystified its pathogenesis. To better understand the pathophysiological mechanisms involved in AFRS, we conducted a prospective, analytical, case-control study involving 40 confirmed immunocompetent AFRS patients and 20 healthy controls. The distribution of Th17 and Treg cells in PBMC, intracellular mRNA expression of retinoid orphan nuclear receptor (RORγt) in Th17 and forkhead transcription factor (FoxP3) in Treg cells, and serum cytokine levels were investigated. Aspergillus flavus was identified from majority (85%) of patient tissue biopsies. Total serum IgE level along with cytokines IL-17, IL-21, IL-1β and TGF-β were comparatively elevated in AFRS. Nevertheless, IL-2 and IL-10 were reduced. Higher percentages of CD3+CD4+ T cells in AFRS with increased expression of CD161 and/or IL-23R markers were observed. Though, lower percentages of CD4+CD25+ Treg cells with elevated expression of GITR were patent. Transcription factor RORγt mRNA was upregulated, whereas FoxP3 mRNA was downregulated in AFRS patients. This inclination of Th17/Treg balance towards Th17, and the proposed role of Tregs on Th1 and Th2 cells in AFRS, directed us to conclude that Aspergillus infestation may lead to development of atopy and immunological dysbalance inciting a Th17 driven response, thereby, promoting aggravation of nasal polyposis. The observation may provide new insight into the molecular mechanisms leading to revision of the classical paradigm.

Protective role of 6-formylindolo[3,2-b]carbazole (FICZ), an endogenous ligand for arylhydrocarbon receptor, in chronic mite-induced dermatitis

BackgroundChronic eczema such as atopic dermatitis imposes significant socio-econo-psychologic burdens on the affected individuals. In addition to conventional topical treatments, phototherapy is recommended for patients with extensive lesions. Although immunosuppression is believed to explain its primary effectiveness, the underlying mechanisms of phototherapy remain unsolved. Ultraviolet irradiation generates various tryptophan photoproducts including 6-formylindolo[3,2-b]-carbazole (FICZ). FICZ is known to be a potent endogenous agonist for aryl hydrocarbon receptor (AHR); however, the biological role of FICZ in chronic eczema is unknown. ObjectiveTo investigate the effect of FICZ on chronic eczema such as atopic dermatitis. MethodsWe stimulated HaCaT cells and normal human epidermal keratinocytes (NHEKs) with or without FICZ and then performed quantitative reverse transcriptase polymerase chain reaction, immunofluorescence, and siRNA treatment. We used the atopic dermatitis-like NC/Nga murine model and treated the mice for 2 weeks with either Vaseline® as a control, FICZ ointment, or betamethasone 17-valerate ointment. The dermatitis score, transepidermal water loss, histology, and expression of skin barrier genes and proteins were evaluated. ResultsFICZ significantly upregulated the gene expression of filaggrin in both HaCaT cells and NHEKs in an AHR-dependent manner, but did not affect the gene expression of other barrier-related proteins. In addition, FICZ improved the atopic dermatitis-like skin inflammation, clinical scores, and transepidermal water loss in NC/Nga mice compared with those of control mice. On histology, FICZ significantly reduced the epidermal and dermal thickness as well as the number of mast cells. Topical FICZ also significantly reduced the gene expression of Il22. ConclusionThese findings highlight the beneficial role of FICZ-AHR and provide a new strategic basis for developing new drugs for chronic eczema.

Atopic Sensitization and Inflammation in Depressed versus Non-depressed Asthmatic Children

Atopic Sensitization and Inflammation in Depressed versus Non-depressed Asthmatic Children

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

Balneotherapeutic effects of high mineral spring water on the atopic dermatitis-like inflammation in hairless mice via immunomodulation and redox balance

BackgroundAtopic dermatitis (AD) is a chronic relapsing allergic inflammatory skin disease that currently affects millions of children and adults worldwide. Drugs used to treat these inflammatory diseases include anti-histamines, corticosteroids and calcineurin inhibitors but these drugs have their limitations such as adverse effects with their long-term usage. Thus, researcher’s interest in several alternative and complementary therapies are continually growing and balneotherapy is one of these approaches. Therefore, we investigate the bathing effect of high concentration mineral spring water (HMW) on redox balance and immune modulation in 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis like inflammation in hairless mice.MethodsWe induced AD-like inflammation by application of DNCB on the dorsal skin of female skh-1 hairless mice. The mice were treated with 100% pure HMW (PHMW) and 10% diluted HMW (DHMW) through bathing once a day for 4 weeks. Tacrolimus ointment (0.1%) was used as positive control (PC) and only DNCB treatment as negative control (NeC) group. The severity of skin lesion inflammation was assessed through clinical scoring and observing scratching behavior. Levels of immunoglobulin E (IgE) and inflammatory cytokines in serum were detected by ELISA and multiplex bead array system, and the levels of oxidative stress-related biomarkers and antioxidant enzyme were also measured.ResultsWe found that HMW significantly decreased the scratching behavior in PHMW and DHMW groups at the 2nd week and in PHMW group at 4th week compared to NeC group. Likewise, serum IgE level was significantly decreased in DHMW group as compared to NeC group. In line, the level of inflammatory cytokines in serum such as interleukin (IL)-1β, IL-13 and tumor necrosis factor-α were significantly inhibited in PHMW and DHMW groups compared to NeC group. In parallel, total reactive oxygen species (ROS) of serum level was significantly decreased in PHMW treatment groups compared to NeC group. Consistently, serum malondialdehyde (MDA) level in PHMW group was lower than in NeC group. By contrast, glutathione peroxidase (GPx) activity was significantly enhanced in PHMW than NeC.ConclusionCollectively, our study indicates a balneotherapeutic effect of HMW on DNCB-induced AD like inflammation in hairless mice via immunomodulation and redox balance.

IL-17A induces heterogeneous macrophages, and it does not alter the effects of lipopolysaccharides on macrophage activation in the skin of mice

Macrophages are central to inflammatory response and become polarized towards the M1 or M2 states upon activation by immunostimulants. In this study, we investigated the effects of lipopolysaccharides (LPS) and interleukin (IL)-17A on the activation of macrophages in in vivo mouse skin. We examined whether macrophages are activated in the skin of imiquimod (IMQ)-treated mice, a model for IL-17A-induced psoriasis-like skin inflammation, and flaky-tail (Flgft) mice, a model for IL-17A-induced chronic atopic dermatitis-like skin inflammation. LPS and IL-17A independently increased the expression levels of iNOS, CX3CR1, CD206, phospho-STAT1 and phospho-STAT3 proteins in the skin of B6 mice, and the effects of LPS was not altered by IL-17A. The expression levels of these proteins were increased in the skin of IMQ-treated and Flgft mice. IL-17A neutralization increased the expressions of iNOS and phospho-STAT1 in the IMQ-treated skin, but it decreased the expressions of CD206 and phospho-STAT3 proteins in the skin of Flgft mice, suggesting that macrophages to change from the M2 to the M1 state in the skin of these mice. These results suggest that IL-17A is involved in the activation of macrophages that are in the process of adopting the heterogeneous profiles of both the M1 and M2 states.

367 CCL17 and CCL22 production induced by toll like receptor stimulation by monocyte-derived Langerhans cells in patients with atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disease that is characterized by recurrent dermatitis, itchiness and high serum levels of IgE. CCL17 and CCL22 are the chemokines that attract and activate CCR4+ cells. We found the monocyte- derived dendritic cells (MoDCs) of AD patients secreted high levels of both CCL17 and CCL22. The toll-like receptor (TLR) family consists of 13 members and several ligands recognized by the TLR family have been identified. TLR2, for example, responds to lipoproteins and peptidoglycans (PGNs) from gram-positive bacteria, whereas TLR4 mediates LPS induces the production of pro-inflammatory and immune-related cytokines. Staphylococcus aureus is also reported to contribute to the exacerbation of AD skin lesion. We performed in vitro experiments to investigate the spontaneous production of CCL17 and CCL22 production by MoLCs. We next examined the effects of toll like receptor agonists on the production of Th2 chemokines by the MoLCs of AD patients. The present study was approved by the ethical committee of Saitama Medical University. We first examined whether the MoLCs of AD patients and HCs produced the CCL17 and CCL22 chemokines. We confirmed that the average amounts of CCL17 and CCL22 were significantly higher in AD patients than in HCs (p<0.01, p<0.01, respectively). We next examined whether the TLR ligands induce CCL17 and CCL22 production by the MoLCs of AD patients. LPS, Pam3CSK4 and poly I:C tended to increase the production of CCL17 and CCL22, while PGN was found to significantly enhance the production of both CCL17 and CCL22 in the MoLCs of AD patients. These data suggest that atopic inflammation is strongly influenced by innate immunity and that these molecules will be the target in the future treatment of atopic dermatitis.

Conditional knock out of N-WASP in keratinocytes causes skin barrier defects and atopic dermatitis-like inflammation

Neural-Wiskott Aldrich Syndrome Protein (N-WASP) is expressed ubiquitously and regulates actin cytoskeleton remodeling. In order to characterize the role of N-WASP in epidermal homeostasis and cutaneous biology, we generated conditional N-WASP knockout mouse using CK14-cre (cytokeratin 14) to ablate expression of N-WASP in keratinocytes. N-WASPK14KO (N-WASPfl/fl; CK14-Cre) mice were born following Mendelian genetics suggesting that N-WASP expression in keratinocytes is not essential during embryogenesis. N-WASPK14KO mice exhibited stunted growth, alopecia, dry and wrinkled skin. The dry skin in N-WASPK14KO mice is probably due to increased transepidermal water loss (TEWL) caused by barrier function defects as revealed by dye penetration assay. N-WASPK14KO mice developed spontaneous inflammation in the neck and face 10 weeks after birth. Histological staining revealed thickening of the epidermis, abnormal cornified layer and extensive infiltration of immune cells (mast cells, eosinophils and T-lymphocytes) in N-WASPK14KO mice skin compared to control mice. N-WASPK14KO mice had higher serum levels of IL-1α, TNF-α, IL-6 and IL-17 compared to control mice. Thus our results suggest that conditional N-WASP knockout in keratinocytes leads to compromised skin barrier, higher infiltration of immune cells and hyperproliferation of keratinocytes due to increased production of cytokines highlighting the importance of N-WASP in maintaining the skin homeostasis.

Evolving Concepts in Atopic Dermatitis.

Tremendous advances have been made in the field of atopic dermatitis in the past 5years. We will explore developments in burden of disease, co-morbidities, pathogenesis, prevention, and management. The tremendous burden moderate to severe atopic dermatitis (AD) places on families from a medical, psychosocial, and financial perspective has been characterized. Epidemiologic studies have identified intriguing new associations beyond the well-characterized "atopic march" of food allergies, asthma, and hay fever. Studies of primary prevention have gained traction including the remarkable impacts of early emollient therapy. Basic advances have simultaneously elucidated the nature of atopic inflammation, setting the stage for an explosion of new potential therapeutic targets. After a fallow period of nearly 15years without a substantial therapeutic advance, this year has already seen two new FDA-approved treatments for AD. AD has a tremendous impact on quality of life with an underappreciated burden of disease; there are important newly described co-morbidities including ADHD and anemia; new insights into etio-pathogenesis have paved the way for novel topical therapies like crisaborole, and new systemic interventions like dupilumab.

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.

Keratinocyte-specific deletion of STAT3 promotes elevated serum IgE in response to Staphylococcus aureus exposure: relevance to hyper-IgE syndrome

Abstract Autosomal dominant hyper-IgE syndrome is caused by STAT3 loss-of-function mutations, which results in a constellation of clinical features, including highly elevated serum IgE levels, a severe eczema-like skin eruption, and an increased susceptibility to Candida albicans and Staphylococcus aureus skin infections. However, the mechanism by which these individuals have elevated IgE levels is not well understood. To evaluate the role of defective STAT3 signaling in contributing to IgE production, we used a mouse model of atopic dermatitis-like skin inflammation induced by epicutaneous exposure to S. aureus in cre/lox mice with cell specific deletion of STAT3. Unexpectedly, STAT3 deletion in keratinocytes (K5-creERT2 × STAT3fl/fl mice) but not in T cells (CD4-creERT2 × STAT3fl/fl mice) resulted in a substantial elevation of serum IgE levels. The increase in serum IgE involved concomitant increase in IgG and IgA levels that were also significantly higher in the keratinocyte-specific STAT3-deficient mice compared with wildtype mice. CD4+ T cells were required for the IgE production, since CD4+ T cell depletion resulted in significantly reduced level of serum IgE in the K5-creERT2 × STAT3fl/fl mice. Taken together, these results indicate that keratinocytes can modulate serum antibody levels, especially in the absence of STAT3 signaling. These results provide an explanation of the increased serum IgE levels in autosomal dominant hyper-IgE syndrome and more broadly into the mechanisms that promote antibody production in response to epicutaneous exposure to microbes and inflammation.

Regulation of Th2 responses by different cell types expressing the interleukin-31 receptor

BackgroundInterleukin-31 (IL-31) is a recently identified cytokine produced by Th2 cells that is involved in the development of atopic dermatitis-induced skin inflammation and pruritus. Its receptor, IL-31RA, is expressed by a number of cell types, including epithelial cells, eosinophils, and activated monocytes and macrophages. To date, however, the regulation of Th2 responses by distinct cell types and tissues expressing IL-31RA has not been well studied.MethodsIn this study, Cry j 2, one of the major allergens of Japanese cedar pollen, was administered to IL-31RA-deficient or wild-type (WT) mice via nasal or intraperitoneal injection for induction of specific Th2 responses.ResultsAfter nasal administration of Cry j 2, IL-31RA-deficient mice showed lower Cry j 2-specific CD4+ T cell proliferation, Th2 cytokine (IL-5 and IL-13) production, and Th2-mediated (IgE, IgG1, and IgG2b) antibody responses than WT mice. In contrast, IL-31RA-deficient mice administered Cry j 2 intraperitoneally showed stronger Th2 immune responses than WT mice.ConclusionsThese results indicate that IL-31R signaling positively regulates Th2 responses induced by nasal administration of Cry j 2, but negatively regulates these responses when Cry j 2 is administered intraperitoneally. Collectively, these data indicate that the induction of antigen-specific Th2 immune responses might depend on tissue-specific cell types expressing IL-31RA.

617 Basophils release amphiregulin and may contribute to murine models of prurigo reaction and MC903-induced atopic dermatitis-like skin inflammation

617 Basophils release amphiregulin and may contribute to murine models of prurigo reaction and MC903-induced atopic dermatitis-like skin inflammation

Rapid adiposity growth increases risks of new-onset asthma and airway inflammation in children.

We aim to (1) examine the influence of long-term adiposity status/short-term adiposity changes on asthma with high or low fractional exhaled nitric oxide (FeNO), and (2) to determine the differences in long-term adiposity status/short-term adiposity changes on atopy, airway inflammation and pulmonary function. We recruited 2450 fourth- to sixth-grade children from the nationwide Taiwan Children Health Study. Data regarding various adiposity indicators, atopic status, pulmonary function tests and asthma outcomes were collected annually. New-onset asthma was stratified by airway inflammation status using FeNO. The generalized estimating equation was used for analyzing longitudinal relationships between long-term adiposity status/short-term adiposity changes and new-onset asthma. Individual adiposity growth slopes were obtained using a hierarchical linear model to establish the relationships between short-term adiposity changes and asthma among children with high airway inflammation. We found long-term adiposity status predicted childhood asthma with low FeNO, whereas short-term adiposity changes may increase risks of childhood asthma with high FeNO. Long-term adiposity status reduced pulmonary function, whereas short-term adiposity increase were associated with atopic diseases and airway inflammation. Obesity-induced asthma could be mediated by high or low airway inflammation, depending on the velocity of increase in adiposity. Rapid adiposity growth may increase risks of childhood asthma and airway inflammation.

Establishing a Role for Interleukin-17 in Atopic Dermatitis-Related Skin Inflammation.

Although CD4+ T cells are known to contribute to the pathology of atopic dermatitis (AD), the role of T helper 17 cells and interleukin (IL)-17 in skin inflammation remains poorly understood. The aim of this study was to characterize the role of IL-17 in AD-related inflammation and immunopathology. Blood samples were collected from 87 children with AD and 60 healthy control subjects. In addition, 10 skin biopsies from each group were collected. Skin and serum expression levels of IL-17 were analyzed by immunohistochemistry and enzyme-linked immunosorbent assay, respectively. 2,4-Dinitrochlorobenzene (DNCB)-sensitized IL-17 knockout and wild-type mice were used as an animal model of skin AD. The messenger ribonucleic acid expression levels of T helper types 1 and 2 cytokines isolated from mouse skin biopsies were determined by quantitative polymerase chain reaction. Cytokine expression profiles of concanavalin A-stimulated splenocytes and IL-17-treated HaCaT keratinocytes were determined. IL-17 expression levels were significantly elevated in the skin, but not in the serum, of patients with AD compared with healthy control subjects. Compared with control subjects, skin lesions from AD animal models exhibited significantly reduced epidermal and dermal thicknesses, as well as reduced messenger ribonucleic acid expression levels of T helper type 2 cytokines IL-4 and IL-13. Concanavalin A-stimulated splenocytes isolated from DNCB-treated IL-17 knockout mice showed significantly less production of IL-4 and IL-5 compared with wild-type controls. IL-6 and IL-8 production by IL-17-stimulated HaCaT cells was blocked by inhibitors of p38 kinase and extracellular signal-regulated kinase. IL-17 may mediate AD-related immune dysregulation by amplifying the inflammatory response.

Bee Venom Phospholipase A2 Ameliorates House Dust Mite Extract Induced Atopic Dermatitis Like Skin Lesions in Mice.

Atopic dermatitis (AD) is a biphasic inflammatory skin disease that is provoked by epidermal barrier defects, immune dysregulation, and increased skin infections. Previously, we have demonstrated that bvPLA2 evoked immune tolerance by inducing regulatory T cells (Treg), and thus alleviated Th2 dominant allergic asthma in mice. Here, we would like to determine whether treatment with bvPLA2 exacerbates the AD-like allergic inflammations induced by house dust mite extract (DFE) in a murine model. Epidermal thickness, immune cell infiltration, serum immunoglobulin, and cytokines were measured. Ear swelling, skin lesions, and the levels of total serum IgE and Th1/Th2 cytokines were elevated in DFE/DNCB-induced AD mice. Topical application of bvPLA2 elicited significant suppression of the increased AD symptoms, including ear thickness, serum IgE concentration, inflammatory cytokines, and histological changes. Furthermore, bvPLA2 treatment inhibited mast cell infiltration into the ear. On the other hand, Treg cell depletion abolished the anti-atopic effects of bvPLA2, suggesting that the effects of bvPLA2 depend on the existence of Tregs. Taken together, the results revealed that topical exposure to bvPLA2 aggravated atopic skin inflammation, suggesting that bvPLA2 might be a candidate for the treatment of AD.