Thymic Stromal Lymphopoietin Expression Research Articles

Thymic Stromal Lymphopoietin Activates Mouse Dendritic Cells Through the JAK/SYK Pathway in Promoting Th17 Response in Psoriasis.

Psoriasis is a chronic inflammatory skin disease that has no cure. While the specific cause of psoriasis is unknown, interactions between immune cells and inflammatory cytokines are believed to be important in its pathogenesis. Thymic stromal lymphopoietin (TSLP) is a cytokine produced by epithelial cells that profoundly affects dendritic cells (DCs) and is involved in allergy and inflammatory diseases. In some studies, its expression is higher in the skin of psoriasis patients, whereas it is increased in treated psoriasis patients when compared with untreated patients in others. To investigate the role of TSLP in the pathogenesis of psoriasis. In vitro and in vivo study. To investigate the effect of TSLP on psoriasis in vivo, a mouse psoriasis model and shRNA targeting TSLP to reduce its expression were used. Mouse primary bone marrow dendritic cells (BMDCs) were cultured in vitro and used to investigate the signaling pathways activated by TSLP. Results: We found that reducing TSLP expression in psoriasis skin alleviated disease severity. TSLP activated the Janus kinase (JAK)/SYK pathway in psoriatic skin. In vitro studies with BMDCs demonstrated that TSLP increased DC maturation through the JAK/SYK pathway and activated DCs-secreted cytokines that stimulated CD4+ T cells to develop into T helper 17 (Th17) cells by activating STAT3 signaling. The JAK/SYK pathway inhibitor reduced the effect of TSLP on activating BMDCs and promoting Th17 differentiation by CD4+ T cells. These findings indicated that TSLP exerted its immune-modulating effect in psoriasis through the JAK/SYK pathway.

Multifactorial Causes and Consequences of TLSP Production, Function, and Release in the Asthmatic Airway.

Disruption of the airway epithelium triggers a defensive immune response that begins with the production and release of alarmin cytokines. These epithelial-derived alarmin cytokines, including thymic stromal lymphopoietin (TSLP), are produced in response to aeroallergens, viruses, and toxic inhalants. An alarmin response disproportionate to the inhaled trigger can exacerbate airway diseases such as asthma. Allergens inhaled into previously sensitized airways are known to drive a T2 inflammatory response through the polarization of T cells by dendritic cells mediated by TSLP. Harmful compounds found within air pollution, microbes, and viruses are also triggers causing airway epithelial cell release of TSLP in asthmatic airways. The release of TSLP leads to the development of inflammation which, when unchecked, can result in asthma exacerbations. Genetic and inheritable factors can contribute to the variable expression of TSLP and the risk and severity of asthma. This paper will review the various triggers and consequences of TSLP release in asthmatic airways.

Endoplasmic reticulum stress enhances the expression of TLR3-induced TSLP by airway epithelium.

Thymic stromal lymphopoietin (TSLP) is an epithelial-derived pleiotropic cytokine that regulates T-helper 2 (Th2) immune responses in the lung and plays a major role in severe uncontrolled asthma. Emerging evidence suggests a role for endoplasmic reticulum (ER) stress in the pathogenesis of asthma. In this study, we determined if ER stress and the unfolded protein response (UPR) signaling are involved in TSLP induction in the airway epithelium. For this, we treated human bronchial epithelial basal cells and differentiated primary bronchial epithelial cells with ER stress inducers and the TSLP mRNA and protein expression was determined. A series of siRNA gene knockdown experiments were conducted to determine the ER stress-induced TSLP signaling pathways. cDNA collected from asthmatic bronchial biopsies was used to determine the gene correlation between ER stress and TSLP. Our results show that ER stress signaling induces TSLP mRNA expression via the PERK-C/EBP homologous protein (CHOP) signaling pathway. AP-1 transcription factor is important in regulating this ER stress-induced TSLP mRNA induction, though ER stress alone cannot induce TSLP protein production. However, ER stress significantly enhances TLR3-induced TSLP protein secretion in the airway epithelium. TSLP and ER stress (PERK) mRNA expression positively correlates in bronchial biopsies from participants with asthma, particularly in neutrophilic asthma. In conclusion, these results suggest that ER stress primes TSLP that is then enhanced further upon TLR3 activation, which may induce severe asthma exacerbations. Targeting ER stress using pharmacological interventions may provide novel therapeutics for severe uncontrolled asthma.NEW & NOTEWORTHY TSLP is an epithelial-derived cytokine and a key regulator in the pathogenesis of severe uncontrolled asthma. We demonstrate a novel mechanism by which endoplasmic reticulum stress signaling upregulates airway epithelial TSLP mRNA expression via the PERK-CHOP signaling pathway and enhances TLR3-mediated TSLP protein secretion.

Anti‐inflammatory control of human skin keratinocytes by targeting nuclear transport checkpoint

AbstractBackgroundIn the two common inflammatory skin diseases, Atopic Dermatitis (AD) and Psoriasis (Ps), keratinocytes (KCs) respond to immune insults through activation of proinflammatory transcription factors (TFs) and their translocation to the cell’s nucleus. Therein, the TFs induce expression of genes encoding mediators of skin inflammation. The Nuclear Transport Checkpoint Inhibitors (NTCIs) were developed to regulate nuclear translocation of activated TFs, the essential step of inflammatory response. This new class of cell‐penetrating peptide therapeutics controls inflammation caused by allergic, autoimmune, metabolic, and microbial insults. In preclinical model of AD, the treatment with NTCI, cSN50.1 peptide, suppressed the expression of Thymic Stromal Lymphopoietin (TSLP), the key gene in the development of allergic inflammation, among the 15 genes silenced by the NTCI. Here, we report the mechanism of anti‐inflammatory action of NTCI in human skin‐derived KCs.ObjectivesWe aimed to determine whether the NTCI treatment can protect human KCs from harmful inflammatory insults.MethodsHuman primary KCs were pretreated with NTCI and challenged with the mix of cytokines Tumour Necrosis Factor alpha (TNF‐α) and Interleukin (IL)‐17A, or with Phorbol 12‐Myristate 13‐Acetate (PMA), and analysed for nuclear content of TFs and the expression of genes encoding mediators of inflammation.ResultsThe nuclear import of TFs, Nuclear Factor ĸB (NF‐ĸB) and Signal Transduction and Activator of Transcription 3 (STAT3), was inhibited in cells treated with NTCI. The expression of TSLP, along with genes encoding the core mediators of inflammation (TNF, IL1B, and IL6) was suppressed by NTCI. Noteworthy, NTCI silenced genes encoding Granulocyte‐Macrophage Colony‐Stimulating Factor (CSF2), and chemokine IL‐8 (CXCL8), responsible for skin infiltration by the eosinophils and other myelomonocytic cells.ConclusionThe control of inflammatory response in human KCs by NTCI is attributed to the inhibition of nuclear import of proinflammatory TFs. The protection of human KCs by NTCI, adds new perspectives to the completed Phase two clinical trial of the NTCI (AMTX‐100 CF) for AD (NCT04313400).

Group III secreted phospholipase A2 -driven lysophospholipid pathway protects against allergic asthma.

Asthma is a chronic inflammatory disease of the airways characterized by recurrent episodes of airway obstruction, hyperresponsiveness, remodeling, and eosinophilia. Phospholipase A2 s (PLA2 s), which release fatty acids and lysophospholipids from membrane phospholipids, have been implicated in exacerbating asthma by generating pro-asthmatic lipid mediators, but an understanding of the association between individual PLA2 subtypes and asthma is still incomplete. Here, we show that group III-secreted PLA2 (sPLA2 -III) plays an ameliorating, rather than aggravating, role in asthma pathology. In both mouse and human lungs, sPLA2 -III was expressed in bronchial epithelial cells and decreased during the asthmatic response. In an ovalbumin (OVA)-induced asthma model, Pla2g3-/- mice exhibited enhanced airway hyperresponsiveness, eosinophilia, OVA-specific IgE production, and type 2 cytokine expression as compared to Pla2g3+/+ mice. Lipidomics analysis showed that the pulmonary levels of several lysophospholipids, including lysophosphatidylcholine, lysophosphatidylethanolamine, and lysophosphatidic acid (LPA), were decreased in OVA-challenged Pla2g3-/- mice relative to Pla2g3+/+ mice. LPA receptor 2 (LPA2 ) agonists suppressed thymic stromal lymphopoietin (TSLP) expression in bronchial epithelial cells and reversed airway hyperresponsiveness and eosinophilia in Pla2g3-/- mice, suggesting that sPLA2 -III negatively regulates allergen-induced asthma at least by producing LPA. Thus, the activation of the sPLA2 -III-LPA pathway may be a new therapeutic target for allergic asthma.

TSLP enhances progestin response in endometrial cancer via androgen receptor signal pathway.

The enriched proteins within in vitro fertilisation (IVF)-generated human embryonic microenvironment could reverse progestin resistance in endometrial cancer (EC). The expression of thymic stromal lymphopoietin (TSLP) in EC was evaluated by immunoblot and IHC analysis. Transcriptome sequencing screened out the downstream pathway regulated by TSLP. The role of TSLP, androgen receptor (AR) and KANK1 in regulating the sensitivity of EC to progestin was verified through a series of in vitro and in vivo experiments. TSLP facilitates the formation of a BMP4/BMP7 heterodimer, resulting in activation of Smad5, augmenting AR signalling. AR in turn sensitises EC cells to progestin via KANK1. Downregulation of TSLP, loss of AR and KANK1 in EC patients are associated with tumour malignant progress. Moreover, exogenous TSLP could rescue the anti-tumour effect of progestin on mouse in vivo xenograft tumour. Our findings suggest that TSLP enhances the sensitivity of EC to progestin through the BMP4/Smad5/AR/KANK1 axis, and provide a link between embryo development and cancer progress, paving the way for the establishment of novel strategy overcoming progestin resistance using embryo original factors.

Resveratrol modulates the Nrf2/NF-κB pathway and inhibits TSLP-mediated atopic march.

Resveratrol has been found to have anti-inflammatory and anti-allergic properties. The effects of resveratrol on thymic stromal lymphopoietin (TSLP)-mediated atopic march remain unclear. To explore the potential role of resveratrol in TSLP-mediated atopic march. The atopic march mouse model was established by topical application of MC903 (a vitamin D3 analog). Following the treatment with resveratrol, airway resistance in mice was discovered by pulmonary function apparatus, and the number of total cells, neutrophils, and eosinophils in bronchoalveolar lavage fluid was counted. The histopathological features of pulmonary and ear skin tissues, inflammation, and cell infiltration were determined by hematoxylin and eosin staining. The messenger RNA (mRNA) levels of TSLP, immunoglobulin E, interleukin (IL)-4, IL-5, and IL-13 were measured by real-time quantitative polymerase chain reaction. The protein expression of nuclear factor kappa B (NF-κB)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling-associated molecules (p-p65, p65, p-I kappa B kinase alpha (IκBα), IκBα, Nrf2, and TSLP) in lung and ear skin tissues were assessed by Western blot analysis. Resveratrol attenuated airway resistance and infiltration of total cells, eosinophils, and neutrophils in both lung and ear skin tissues. Resveratrol ameliorates serum inflammatory markers in allergic mice. Moreover, the phosphorylation levels of NF-κB pathway-related proteins were significantly reduced by administration of resveratrol in allergic lung and ear skin tissues. Similarly, the protein expression of TSLP in both lung and ear skin tissues was reduced by resveratrol, and Nrf2, a protector molecule, was increased with resveratrol treatment. Resveratrol attenuates TSLP-reduced atopic march through ameliorating inflammation and cell infiltration in pulmonary and ear skin tissues by inhibiting the abnormal activation of NF-κB signaling pathway.

Mechanism underlying pruritus in recessive dystrophic epidermolysis bullosa: Role of interleukin-31 from mast cells and macrophages.

Pruritus is a highly burdensome symptom in patients with epidermolysis bullosa, especially recessive dystrophic epidermolysis bullosa (RDEB); however, only a few studies have assessed the molecular pathogenesis of RDEB-associated pruritus. Interleukin (IL)-31 is a key cytokine implicated in pruritus associated with dermatologic diseases such as atopic dermatitis and prurigo nodularis. To investigate the role and cellular source of IL-31 in RDEB-associated pruritus. Serum and skin samples were obtained from 11 RDEB patients and 11 healthy controls. Pruritus visual analogue scale scores were determined. Serum levels of IL-31 and thymic stromal lymphopoietin (TSLP) were examined by enzyme-linked immunosorbent assay (ELISA). The expression of IL-31 and other pruritus mediators in the skin were examined through immunofluorescence staining, and their correlation with pruritus severity was analysed. Serum IL-31 and TSLP were elevated in RDEB patients. IL-31 expression was increased in RDEB skin and positively correlated with pruritus severity. Most of the IL-31-expressing cells were mast cells, and some were CD206(+) M2-like macrophages. The number of substance P(+) cells was also increased in the patients' skin, and most of them were mast cells. The number of substance P(+) mast cells was correlated with the number of IL-31(+) dermal infiltrates. The number of IL-4Rα- and IL-13-expressing cells and expression of TSLP and periostin increased in RDEB skin, but without a correlation to pruritus score. The increased production of skin IL-31 from mast cells and M2-like macrophages may be the mechanism underlying pruritus in RDEB.

Antibody targeting TSLP suppresses DSS-induced colitis and activation of the JAK2/STAT5 pathway in mice.

There is currently no safe or effective treatment for inflammatory bowel disease (IBD), which is defined as recurrent and persistent intestinal inflammation. Thymic stromal lymphopoietin (TSLP) has been shown to be associated with the pathogenesis of IBD, and the JAK2/STAT5 signalling pathway has demonstrated much promise as a novel therapeutic target for IBD. In this study, we first evaluated levels of TSLP in dextran sodium sulphate (DSS)-induced IBD mice. Second, we applied tezepelumab, an anti-TSLP monoclonal antibody (20μg per mouse, intraperitoneally), to DSS-induced IBD mice and quantified the signs of histopathological change, intestinal inflammation, and integrity of the mucosal barrier. In addition, the effect of DSS and/or tezepelumab on the phosphorylation of the JAK/STAT pathway was investigated. TSLP expression levels were elevated in DSS-induced IBD mice, whereas TSLP antibody treatment suppressed the pathological features associated with IBD and alleviated intestinal inflammation and mucosal barrier disruption. Moreover, level of phosphorylated JAK2/STAT5 were increased in DSS-induced IBD mice, but were strongly decreased in the presence of tezepelumab. Our findings suggest that targeting TSLP via the JAK2/STAT5 signalling pathway may be an effective approach for the treatment of IBD.

An atopic dermatitis-like murine model by skin-brushed cockroach Per a 2 and oral tolerance induction by Lactococcus lactis-derived Per a 2.

Atopic dermatitis (AD) is a complex, chronic inflammatory skin disease. An estimated 57.5% of asthmatic patients and 50.7% of rhinitis patients are allergic to cockroaches in Taiwan. However, the role of cockroaches in the pathogenesis of AD is undetermined. Oral tolerance might be another strategy for protecting against AD and allergic inflammation by regulating T helper 2 (Th2) immune responses. Aim to examine the underlying immunologic mechanism, we developed an AD-like murine model by skin-brushing with cockroach Per a 2. We also investigated whether the systemic inflammation of AD in this murine model could be improved by specific tolerance to Lactococcus lactis-expressing Per a 2, which was administered orally. Repeated painting of Per a 2 without adjuvant to the skin of mice resulted in increased total IgE, Per a 2-specific IgE, and IgG1, but not IgG2a. In addition, epidermal thickening was significantly increased, there were more scratch episodes, and there were increases in total white blood cells (eosinophil, neutrophil, and lymphocyte) and Th2 cytokines (Interleukin (IL)-4, IL-5, IL-9, and IL-13) in a dose-dependent manner. The results revealed that oral administration of L. lactis-Per a 2 ameliorated Per a 2-induced scratch behavior and decreased the production of total IgE, Per a 2-specific IgE, and IgG1. Furthermore, L. lactis-Per a 2 treatment also suppressed inflammatory infiltration, expressions of thymic stromal lymphopoietin (TSLP) and IL-31 in skin lesions, and downregulated splenic IL-4 and IL-13 in Per a 2-induced AD mice. This study provides evidence supporting that repeated brushing of aeroallergens to the skin leads to atopic dermatitis phenotypes and oral allergen-specific immune tolerance can ameliorate AD-like symptoms and systemic inflammation and prevent progression of atopic march.

House dust mite disrupts the airway epithelial barrier by affecting the expression of thymic stromal lymphopoietin through inducing Atg5.

House dust mite disrupts the airway epithelial barrier by affecting the expression of thymic stromal lymphopoietin through inducing Atg5.

Integration analysis using bioinformatics and experimental validation on the clinical and biological significance of TSLP in cancers

Thymic stromal lymphopoietin (TSLP) has significantly impacted the development and progression of various neoplastic disorders. To comprehensively evaluate the diverse significance of TSLP in malignant tumors, we first integrative analyze the TSLP expression level in paired and unpaired pan-cancer tissue and cell line, compared against the normal tissue. The correlation between TSLP expression, molecular subtypes, immune subtypes, diagnostic value, and prognostic value in pan-cancer was also investigated. We then explored the impact of TSLP expression on multifaced immune cell infiltration and subsequent clinical outcomes in lung adenocarcinoma (LUAD) patients. and conducted cellular experiments to functionally examine the effect of TSLP on cell proliferation, apoptosis, cell cycle, migration, and invasion in LUAD. The anti-neoplastic mechanism of TSLP was further investigated by qRT-PCR and western blotting. Our findings reveal that TSLP expression is abnormally low in various cancers compared to normal tissue and is associated with different molecular and immune subtypes of cancers. Moreover, ROC and survival analysis results suggest that TSLP expression is correlated with the diagnostic, prognostic, clinical features, and immune cells of LUAD patients. Cell experiments showed that overexpression of TSLP elicited a significant reduction in LUAD cell viability, promoted cell apoptosis, impeded cell cycle progression in the G2/M phase, and inhibited cell migration and invasion. In addition, TSLP inhibited LUAD progression through the JAK1/STAT3 signaling pathway. Therefore, targeting TSLP shows potential as a therapeutic strategy for pan-cancer, particularly for LUAD, and as a biomarker for predicting the prognosis of this malignancy.

Hypoxia induces the production of epithelial-derived cytokines in eosinophilic chronic rhinosinusitis with nasal polyps.

Hypoxia plays a significant role in the pathogenesis of chronic rhinosinusitis (CRS). However, the role and mechanism of hypoxia in the type 2 immune response in eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) remain unclear. The expression of hypoxia-inducible factor-1α (HIF-1α) and epithelial-derived cytokines (EDCs), including interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP), was detected in nasal polyps via immunohistochemical analysis. The relationship between HIF-1α and EDCs was also elucidated using Pearson's correlation. Moreover, primary human nasal epithelial cells (HNECs) and a mouse model of ECRSwNP were employed to elucidate the role and mechanism of hypoxia in type 2 immune responses. HIF-1α, IL-25, IL-33, and TSLP expression levels were upregulated in the non-ECRSwNP and ECRSwNP groups compared with the control group, with the ECRSwNP group having the highest HIF-1α and EDC expression levels. Additionally, HIF-1α was positively correlated with IL-25 and IL-33 in the ECRSwNP group. Meanwhile, treatment with a HIF-1α inhibitor, PX-478, inhibited the hypoxia-induced increase in the mRNA and protein expression of EDCs and type 2 cytokines in HNECs. Similarly, in vivo, PX-478 inhibited EDC expression in the sinonasal mucosa of mice with ECRSwNP. Hypoxia induces EDC expression by upregulating HIF-1α levels, thereby promoting type 2 immune responses and the development of ECRSwNP. Hence, targeting HIF-1α may represent an effective therapeutic strategy for ECRSwNP.

Identification of potential hub genes associated with atopic dermatitis-like recombinant human epidermal model using integrated transcriptomic and proteomic analysis.

Atopic dermatitis (AD) is a severe inflammatory skin disorder, characterized by elevated levels of proinflammatory cytokines that fuel a vicious cycle of inflammation. While inflammatory recombinant human epidermal (RHE) models relevant to AD have been established, comprehensive understanding remains limited. To illuminate changes and identify potential hub genes involved in AD-related inflammation, RHE models, stimulated by an inflammatory cocktail including polyinosinic-polycytidylic acid, tumor necrosis factor alpha (TNF-α), interleukin 4 (IL-4) and interleukin 13 (IL-13), were constructed and examined using tandem mass tags-proteomic coupled with RNA-seq transcriptomic analyses. Principal component analysis (PCA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway functional enrichment were employed for the analysis of related genes and proteins. Protein-protein interaction networks helped identify hub genes, which were further confirmed by qPCR and western blot. We observed high expression of thymic stromal lymphopoietin in the inflammatory RHE. Our study identified 2369 differentially expressed genes and 880 differentially expressed proteins in the cocktail-induced group versus the normal control group. A total of 248 overlapping symbols were enriched in various biological processes and signaling pathways, including cornification envelope, cell-cell junction, calcium ion binding, extracellular matrix receptor, terpenoid backbone biosynthesis, and peroxisome proliferator-activated receptors signaling pathway, among others. Among the 248 overlapping symbols, CytoHubba identified 10 hub molecules, namely signal transducer and activator of transcription 3 (STAT3), integrin subunit beta 1 (ITGB1), filaggrin (FLG), involucrin (IVL), DEAD (Asp-Glu-Ala-Asp) box polypeptide 58 (DDX58), small proline rich protein 1B (SPRR1B), interferon induced with helicase C domain 1 (IFIH1), desmoglein 1 (DSG1), collagen type XVII alpha 1 chain (COL17A1), and integrin subunit alpha 6 (ITGA6), based on the degree. These integrated results offer valuable insights into the molecular mechanisms of AD and present potential tools for screening cosmetic formulations intended for the treatment of AD.

Exosome from IFN-γ-Primed Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Improved Skin Inflammation and Barrier Function.

The pathogenesis of atopic dermatitis (AD) is multifactorial, including immune dysregulation and epidermal barrier defects, and a novel therapeutic modality that can simultaneously target multiple pathways is needed. We investigated the therapeutic effects of exosomes (IFN-γ-iExo) secreted from IFN-γ-primed induced pluripotent stem cell-derived mesenchymal stem cells (iMSC) in mice with Aspergillus fumigatus-induced AD. IFN-γ-iExo was epicutaneously administered to mice with AD-like skin lesions. The effects of IFN-γ-iExo treatment were investigated through clinical scores, transepidermal water loss (TEWL) measurements, and histopathology. To elucidate the therapeutic mechanism, we used an in vitro model of human keratinocyte HaCaT cells stimulated with IL-4 and IL-13 and performed extensive bioinformatics analysis of skin mRNA from mice. The expression of indoleamine 2,3-dioxygenase was higher in IFN-γ primed iMSCs than in iMSCs. In human keratinocyte HaCaT cells, treatment with IFN-γ-iExo led to decreases in the mRNA expression of thymic stromal lymphopoietin, IL-25, and IL-33 and increases in keratin 1, keratin 10, desmoglein 1, and ceramide synthase 3. IFN-γ-iExo treatment significantly improved clinical and histological outcomes in AD mice, including clinical scores, TEWL, inflammatory cell infiltration, and epidermal thickness. Bioinformatics analysis of skin mRNA from AD mice showed that IFN-γ-iExo treatment is predominantly involved in skin barrier function and T cell immune response. Treatment with IFN-γ-iExo improved the clinical and histological outcomes of AD mice, which were likely mediated by restoring proper skin barrier function and suppressing T cell-mediated immune response.

Effect of Peanut Protein Treated with Alkaline Protease and Flavorzyme on BALB/c Mice.

This article aims to analyze the effects of enzyme treatment concentration, temperature, and time on peanut protein so as to obtain an optimal enzymatic hydrolysis condition for flavorzyme (Fla) and alkaline protease (Alk). The results were as follows: enzymatic hydrolysis temperature 60 °C and 55 °C, enzyme concentration 10% and 4%, enzymatic hydrolysis time 80 min and 60 min, and double enzyme hydrolysis ratio 2% Fla + 5% Alk, respectively. The BALB/c mice were sensitized with gavage of peanut protein before and after enzyme treatment to evaluate the effects of different enzyme treatments on peanut allergenicity. Compared with the mice sensitized with raw peanuts, the weight growth rate of the mice sensitized with enzyme treatment peanut increased but not as much as the control, the degranulation degree of mast cell and basophils decreased, the inflammatory infiltration and congestion in jejunum and lung tissue decreased, the expression of proinflammatory factors and thymic stromal lymphopoietin (TSLP) gene decreased, and the secretion of specific antibodies (IgE, and IgG) decreased, and the binding ability of peanut protein with peanut-specific IgE antibodies decreased as well. The results above indicate that the allergenicity of peanut protein decreases after enzyme treatment and the dual enzyme (Fla + Alk) treatment can be much more efficient.

Thymic stromal lymphopoietin participates in the host response to intra-amniotic inflammation leading to preterm labor and birth

The aim of this study was to establish the role of thymic stromal lymphopoietin (TSLP) in the intra-amniotic host response of women with spontaneous preterm labor (sPTL) and birth. Amniotic fluid and chorioamniotic membranes (CAM) were collected from women with sPTL who delivered at term (n = 30) or preterm without intra-amniotic inflammation (n = 34), with sterile intra-amniotic inflammation (SIAI, n = 27), or with intra-amniotic infection (IAI, n = 17). Amnion epithelial cells (AEC), Ureaplasma parvum, and Sneathia spp. were also utilized. The expression of TSLP, TSLPR, and IL-7Rα was evaluated in amniotic fluid or CAM by RT-qPCR and/or immunoassays. AEC co-cultured with Ureaplasma parvum or Sneathia spp. were evaluated for TSLP expression by immunofluorescence and/or RT-qPCR. Our data show that TSLP was elevated in amniotic fluid of women with SIAI or IAI and expressed by the CAM. TSLPR and IL-7Rα had detectable gene and protein expression in the CAM; yet, CRLF2 was specifically elevated with IAI. While TSLP localized to all layers of the CAM and increased with SIAI or IAI, TSLPR and IL-7Rα were minimal and became most apparent with IAI. Co-culture experiments indicated that Ureaplasma parvum and Sneathia spp. differentially upregulated TSLP expression in AEC. Together, these findings indicate that TSLP is a central component of the intra-amniotic host response during sPTL.

Kaempferol therapy improved MC903 induced-atopic dermatitis in a mouse by suppressing TSLP, oxidative stress, and type 2 inflammation

BackgroundAtopic dermatitis is a common skin disease caused by genetic susceptibility, environmental factors, immune response, and skin barrier dysfunction. Kaempferol is a natural flavonoid widely found in tea, vegetables, and fruits and has been reported to have excellent anti-inflammation activity. However, the therapeutic effect of kaempferol on atopic dermatitis is unclear. ObjectiveThis study aimed to elucidate the effect of kaempferol on skin inflammation in atopic dermatitis. MethodsThe suppressive effect of kaempferol administration on skin inflammation was examined using MC903-induced atopic dermatitis-like skin inflammation mouse model. Quantification of skin dermatitis and transepidermal water loss was performed. A histopathological study was performed to examine thymic stromal lymphopoietin expression, cornified envelope proteins such as filaggrin, loricrin, and involucrin, and the numbers of infiltrating inflammatory cells, including lymphocytes, macrophages, and mast cells in the dermatitis area. The expressions of IL-4 and IL-13 were investigated by qPCR and flow cytometry analysis using skin tissues. The expression of HO-1 was investigated by western blot and qPCR. ResultsKaempferol therapy significantly suppressed MC903-induced dermatitis, TEWL, TSLP, and HO-1 expression, and infiltration of inflammatory cells. Kaempferol therapy improved the decreased expressions of filaggrin, loricrin, and involucrin in MC903-induced dermatitis skin site. The expressions of IL-4, and IL-13 were partially decreased in kaempferol-treated mice. ConclusionKaempferol might improve MC903-induced dermatitis via suppression of type 2 inflammation and improvement of barrier dysfunction by inhibition of TSLP expression and oxidative stress. Kaempferol might have the potential to be a new treatment for atopic dermatitis.

Adipose-derived stem cell exosomes for treatment of dupilumab-related facial redness in patients with atopic dermatitis

BackgroundDupilumab facial redness (DFR) is a side effect of dupilumab treatment that has only been recently reported. We previously reported on two patients with DFR who were successfully treated with a topical formulation containing human adipose tissue-derived mesenchymal stem cell-derived exosomes (ASCEs).ObjectivesThe study aimed to evaluate the efficacy and safety of ASCEs in DFR.Participants and methodsWe performed 12-week prospective study at single center. Twenty adult atopic dermatitis patients diagnosed with DFR were enrolled. They were treated with a topical application of the exosome formulation every week for five consecutive weeks.ResultsAfter exosome treatment, both the average investigator global assessment score and clinical erythema assessment scale scores decreased. 19 patients (95%) were satisfied with the treatment. Compared to baseline, erythema index at week 4 were decreased by 31, 27, 13, and 25 units on the forehead, chin, right and left cheek respectively. The analysis of stratum corneum samples revealed the expression of IL-1α and human thymic stromal lymphopoietin was suppressed after exosome treatment, whereas filaggrin and vascular endothelial growth factor expression increased.ConclusionsThis study suggests topical formulation containing ASCEs can alleviate DFR by downregulating local inflammation and restoring skin barrier function.

Foxp3 and Bcl6 deficiency synergistically induces spontaneous development of atopic dermatitis-like skin disease.

Atopic dermatitis (AD) is a common chronic skin disease caused by immune dysfunction, specifically the hyperactivation of Th2 immunity. AD is a complex disease with multiple factors contributing to its development; however, the interaction between these factors is not fully understood. In this study, we demonstrated that the conditional deletion of both the forkhead box p3 (Foxp3) and B-cell lymphoma 6 (Bcl6) genes induced the spontaneous development of AD-like skin inflammation with hyperactivation of type 2 immunity, skin barrier dysfunction, and pruritus, which were not induced by the single deletion of each gene. Furthermore, the development of AD-like skin inflammation was largely dependent on IL-4/13 signaling but not on immunoglobulin E (IgE). Interestingly, we found that the loss of Bcl6 alone increased the expression of thymic stromal lymphopoietin (TSLP) and interleukin (IL)-33 in the skin, suggesting that Bcl6 controls Th2 responses by suppressing TSLP and IL-33 expression in epithelial cells. Our results suggest that Foxp3 and Bcl6 cooperatively suppress the pathogenesis of AD. Furthermore, these results revealed an unexpected role of Bcl6 in suppressing Th2 responses in the skin.