Hepatic transcriptome delineates the therapeutic effects of Sanren Tang on high-fat diet-induced non-alcoholic fatty liver disease.

OBJECTIVE: To evaluate the effects of Sanren Tang (SRT, ) on a high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in mice and to investigate the hepatic transcriptome regulated by SRT. METHODS: The primary SRT components were identified using ultra-high-performance liquid chromatography-high-resolution accurate mass spectrometry. The SRT-induced pharmacological effects on HFD-induced NAFLD were evaluated in mice for 16 weeks. Obeticholic acid was used as a control drug. Body weight, food intake, and homeostatic model assessment for insulin resistance (HOMA-IR) index were analysed. Hepatic histological changes were observed in haematoxylin and eosin-stained sections and quantified using the NAFLD activity score (NAS). Serum alanine aminotransferase (ALT) and hepatic triglyceride (TG) levels were measured. Lipids in hepatocytes were visualised by Oil red staining. RNA-sequencing was performed to determine the transcriptome profile of the liver tissue. The differentially expressed genes were validated using real-time polymerase chain reaction and Western blotting. RESULTS: Four principal compounds were identified in the SRT: adenosine, amygdalin, luteoloside, and magnolol. SRT ameliorated hepatic histology and lipid deposition in the NAFLD mice, and decreased HOMA-IR, NAS and ALT, and hepatic TG levels. Hepatic transcriptome analysis revealed 232 HFD-regulated genes that were reversed by SRT simultaneously. Retinol metabolism, cytokine-cytokine receptor interaction, and peroxisome proliferator-activated receptor (PPAR) γ signalling were the top three SRT-regulated pathways in NAFLD. CONCLUSIONS: SRT significantly ameliorated HFD-induced NAFLD, which was correlated with the regulation of genes enriched in the retinol metabolism, cytokine-cytokine receptor interaction, and PPARγ signalling pathways.

Dextran-Sulfate-Sodium-Induced Colitis-Ameliorating Effect of Aqueous Phyllanthus emblica L. Extract through Regulating Colonic Cell Gene Expression and Gut Microbiomes.

The anti-inflammation effect of aqueous Phyllanthus emblica L. extract (APE) and its possible underlying mechanism in dextran sulfate sodium (DSS)-induced mice chronic colonic inflammation were studied. APE treatment significantly improved the colitic symptoms, including ameliorating the shortening of the colon, increasing the DSS-induced body weight loss, reducing the disease activity index, and reversing the condition of colon tissue damage of mucus lost and goblet cell reduction. Overproduction of serum pro-inflammatory cytokines were suppressed by the treatment of APE. Gut microbiome analysis showed that APE remodeled the structure of gut bacteria in phylum and genus levels, upregulating the abundance of phylum Bacteroidetes, family Muribaculaceae, and genus Bacteroides and downregulating the abundance of phylum Firmicutes. The reshaped gut microbiome caused metabolic functions and pathway change with enhanced queuosine biosynthesis and reduced polyamine synthesis pathway. Colon tissue transcriptome analysis further elucidated APE-inhibited mitogen-activated protein kinase (MAPK), cytokine-cytokine receptor interaction, and tumor necrosis factor (TNF) signaling pathways and the expressions of the genes that promote the progress of colorectal cancer. It turned out that APE reshaped the gut microbiome and inhibited MAPK, cytokine-cytokine receptor interaction, and TNF signaling pathways as well as the colorectal-cancer-related genes to exert its colitis protective effect.

[Mechanism of artesunate on bone destruction in experimental rheumatoid arthritis based on transcriptomics and network pharmacology].

The present study investigated the mechanism of artesunate in the treatment of bone destruction in experimental rheumatoid arthritis(RA) based on transcriptomics and network pharmacology. The transcriptome sequencing data of artesunate in the inhibition of osteoclast differentiation were analyzed to obtain differentially expressed genes(DEGs). GraphPad Prism 8 software was used to plot volcano maps and heat maps were plotted through the website of bioinformatics. GeneCards and OMIM were used to collect information on key targets of bone destruction in RA. The DEGs of artesunate in inhibiting osteoclast differentiation and key target genes of bone destruction in RA were intersected by the Venny 2.1.0 platform, and the intersection target genes were analyzed by Gene Ontology(GO)/Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment. Finally, the receptor activator of nuclear factor-κB(RANKL)-induced osteoclast differentiation model and collagen-induced arthritis(CIA) model were established. Quantitative real time polymerase chain reaction(q-PCR), immunofluorescence, and immunohistochemistry were used to verify the pharmacological effect and molecular mechanism of artesunate in the treatment of bone destruction in RA. In this study, the RANKL-induced osteoclast differentiation model in vitro was established and intervened with artesunate, and transcriptome sequencing data were analyzed to obtain 744 DEGs of artesunate in inhibiting osteoclast differentiation. A total of 1 291 major target genes of bone destruction in RA were obtained from GeneCards and OMIM. The target genes of artesunate in inhibiting osteoclast differentiation and the target genes of bone destruction in RA were intersected to obtain 61 target genes of artesunate against bone destruction in RA. The intersected target genes were analyzed by GO/KEGG enrichment. According to the results previously reported, the cytokine-cytokine receptor interaction signaling pathway was selected for experimental verification. Artesunate intervention in the RANKL-induced osteoclast differentiation model showed that artesunate inhibited CC chemokine receptor 3(CCR3), CC chemokine receptor 1(CCR1) and leukemia inhibitory factor(LIF) mRNA expression in osteoclasts in a dose-dependent manner compared with the RANKL-induced group. Meanwhile, the results of immunofluorescence and immunohistochemistry showed that artesunate could dose-dependently reduce the expression of CCR3 in osteoclasts and joint tissues of the CIA rat model in vitro. This study indicated that artesunate regulated the CCR3 in the cytokine-cytokine receptor interaction signaling pathway in the treatment of bone destruction in RA and provided a new target gene for the treatment of bone destruction in RA.

Interleukin-19 as an Immunoregulatory Cytokine.

IL-19 is a type of anti-inflammatory cytokine. Since the receptor for IL-19 is common to IL-20 and IL-24, it is important to clarify the role of each of the three cytokines. If three different cytokines bind to the same receptor, these three may have been produced to complement the other two. However, perhaps it is unlikely. Recently, the existence of a novel receptor for IL-19 was suggested. The distinction between the roles of the three cytokines still makes sense. On the other hand, because T cells do not produce IL-19, their role in acquired immunity is limited or indirect. It has been reported that IL-19 causes inflammation in some diseases but does not have an anti-inflammatory effect. In this review, we introduce the current role of IL-19 in each disease. In addition, we will describe the molecular mechanism of IL-19 and its development for the prevention of diseases. IL-19 was previously considered an anti-inflammatory cytokine, but we would like to propose it as an immunoregulatory cytokine.

Acute Effects of the Consumption of Passiflora setacea Juice on Metabolic Risk Factors and Gene Expression Profile in Humans.

BACKGROUND: Passiflora setacea (PS) is a passionfruit variety of the Brazilian savannah and is a rich source of plant food bioactives with potential anti-inflammatory activity. This study aimed to investigate the effect of an acute intake of PS juice upon inflammation, metabolic parameters, and gene expression on circulating immune cells in humans. METHODS: Overweight male volunteers (n = 12) were enrolled in two double-blind placebo-controlled studies. Blood samples were collected from fasting volunteers 3 h after the consumption of 250 mL of PS juice or placebo (PB). Metabolic parameters (insulin, glucose, total cholesterol, high-density lipoprotein (LDL), high-density lipoprotein (HDL), and total triglycerides) and circulating cytokines were evaluated (study 1). Peripheral blood mononuclear cell (PBMC) from the same subjects were isolated and RNA was extracted for transcriptomic analyses using microarrays (study 2). RESULTS: Insulin and homeostatic model assessment for insulin resistance (HOMA-IR) levels decreased statistically after the PS juice intake, whereas HDL level increased significantly. Interleukin (IL)-17A level increased after placebo consumption, whereas its level remained unchanged after PS juice consumption. Nutrigenomic analyses revealed 1327 differentially expressed genes after PS consumption, with modulated genes involved in processes such as inflammation, cell adhesion, or cytokine-cytokine receptor. CONCLUSION: Taken together, these clinical results support the hypothesis that PS consumption may help the prevention of cardiometabolic diseases.

New and Emerging Biologics for Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that is characterized by complex pathophysiology involving both skin barrier dysfunction and aberrant type 2 inflammation/immune responses. AD can be a debilitating condition that drastically impairs quality of life, especially in patients with moderate-to-severe disease. Currently, topical therapies such as corticosteroids and non-steroidal immunomodulatory therapy provide limited efficacy for patients with moderate-to-severe AD; limitations include inadequate response, cutaneous toxicity from overuse, and poor tolerance due to stinging and burning. Historically, the development of targeted therapies has been challenging due to the complex and multifaceted etiology of AD. Recent progress in understanding the immunopathology of AD reinforces the development of newly targeted therapeutics. The successful launch of dupilumab, a monoclonal antibody targeting the interleukin (IL)-4α receptor subunit, for AD in 2017 spurred the development of a number of biologics targeting novel cytokine and receptor targets that are now in phase II and III of development. This review aims to explore the rationale behind these novel biological therapies and to summarize current clinical studies of these agents.

PTPN11 (SHP2) Is Indispensable for Growth Factors and Cytokine Signal Transduction During Bovine Oocyte Maturation and Blastocyst Development.

This study was aimed to investigate the role of SHP2 (Src-homology-2-containing phosphotyrosine phosphatase) in intricate signaling networks invoked by bovine oocyte to achieve maturation and blastocyst development. PTPN11 (Protein Tyrosine Phosphatase, non-receptor type 11) encoding protein SHP2, a positive transducer of RTKs (Receptor Tyrosine Kinases) and cytokine receptors, can play a significant role in bovine oocyte maturation and embryo development, but this phenomenon has not yet been explored. Here, we used different growth factors, cytokines, selective activator, and a specific inhibitor of SHP2 to ascertain its role in bovine oocyte developmental stages in vitro. We found that SHP2 became activated by growth factors and cytokines treatment and was highly involved in the activation of oocyte maturation and embryo development pathways. Activation of SHP2 triggered MAPK (mitogen-activated protein kinases) and PI3K/AKT (Phosphoinositide 3-kinase/Protein kinase B) signaling cascades, which is not only important for GVBD (germinal vesical breakdown) induction but also for maternal mRNA translation. Inhibition of phosphatase activity of SHP2 with PHPS1 (Phenylhydrazonopyrazolone sulfonate 1) reduced oocytes maturation as well as bovine blastocyst ICM (inner cell mass) volume. Supplementation of LIF (Leukemia Inhibitory Factor) to embryos showed an unconventional direct relation between p-SHP2 and p-STAT3 (Signal transducer and activator of transcription 3) for blastocyst ICM development. Other than growth factors and cytokines, cisplatin was used to activate SHP2. Cisplatin activated SHP2 modulate growth factors effect and combine treatment significantly enhanced quality and rate of developed blastocysts.

Short ragweed pollen promotes M2 macrophage polarization via TSLP/TSLPR/OX40L signaling in allergic inflammation.

This study was to explore the role and mechanism of macrophages in pollen-triggered allergic inflammation. A murine model of short ragweed (SRW) pollen-induced experimental allergic conjunctivitis (EAC), and bone marrow (BM)-macrophages cultures were used. Typical allergic manifestations and TSLP-stimulated Th2 hyperresponse were observed in ocular surface of EAC model in wild-type (WT) mice induced by SRW. The M2 phenotype markers, Arg1, Ym1 and FIZZ1, were highly expressed by conjunctiva and draining cervical lymph nodes (CLNs) of WT-EAC mice when compared with controls, as evaluated by RT-qPCR and Immunofluorescent double staining with macrophage marker F4/80. The stimulated expression of TSLPR and OX40L by macrophage was detected in conjunctiva and CLNs by RT-qPCR, double staining, and flow cytometry. M2 macrophages were found to produce TARC and MDC. In contrast, EAC model with TSLPR-/- mice did not show allergic signs and any increase of Th2 cytokines (IL-4, IL-5 and IL-13) and M2 markers. In vitro cultures confirmed that SRW extract stimulates expression of TSLPR, OX40L, TARC, MDC, and three M2 markers by BM-macrophages from WT mice, but not from TSLPR-/- mice. These findings demonstrate that SRW pollen primes macrophage polarization toward to M2 phenotype via TSLP/TSLPR/OX40L signaling to amplify allergic inflammation.

Advanced Molecular Knowledge of Therapeutic Drugs and Natural Products Focusing on Inflammatory Cytokines in Asthma.

Asthma is a common respiratory disease worldwide. Cytokines play a crucial role in the immune system and the inflammatory response to asthma. Abnormal cytokine expression may lead to the development of asthma, which may contribute to pathologies of this disease. As cytokines exhibit pleiotropy and redundancy characteristics, we summarized them according to their biologic activity in asthma development. We classified cytokines in three stages as follows: Group 1 cytokines for the epithelial environment stage, Group 2 cytokines for the Th2 polarization stage, and Group 3 cytokines for the tissue damage stage. The recent cytokine-targeting therapy for clinical use (anti-cytokine antibody/anti-cytokine receptor antibody) and traditional medicinal herbs (pure compounds, single herb, or natural formula) have been discussed in this review. Studies of the Group 2 anti-cytokine/anti-cytokine receptor therapies are more prominent than the studies of the other two groups. Anti-cytokine antibodies/anti-cytokine receptor antibodies for clinical use can be applied for patients who did not respond to standard treatments. For traditional medicinal herbs, anti-asthmatic bioactive compounds derived from medicinal herbs can be divided into five classes: alkaloids, flavonoids, glycosides, polyphenols, and terpenoids. However, the exact pathways targeted by these natural compounds need to be clarified. Using relevant knowledge to develop more comprehensive strategies may provide appropriate treatment for patients with asthma in the future.

Dietary fish oil supplementation alters liver gene expressions to protect against LPS-induced liver injury in weanling piglets.

Here, the potential mechanisms of the protective effects of fish oil against LPS-induced liver injury in a piglet model were investigated by using RNA sequencing. Twenty-four piglets were used in a 2 × 2 factorial design, and the main factors included diet (5% corn oil or 5% fish oil) and immunological challenge (LPS or saline, on d 19). All piglets were slaughtered at 4 h after challenge, and liver samples were collected. Fish oil improved liver morphology and reduced TNF-α, IL-1ß and IL-6 productions after LPS challenge. RNA sequencing analysis showed fish oil had significant effect on the expressions of genes involved in immune response during LPS-induced inflammation. Selected gene expression changes were validated using quantitative RT-PCR. Fish oil reduced the expressions of pro-inflammatory genes IL1R1, IL1RAP, CEBPB and CRP, and increased that of anti-inflammatory genes IL-18BP, NFKBIA, IFIT1, IFIT2 and ATF3. Moreover, fish oil restored the expressions of some lipid metabolism-related genes, such as ACAA1, ACACA, ACADS and ACADM, which were only decreased in pigs fed a corn oil diet after LPS challenge. Our RNA sequencing reveals novel gene-nutrient interactions following fish oil supplementation and evoked inflammation, which add to the current understanding of the benefits of n-3 polyunsaturated fatty acids against liver injury.

From proteomics to discovery of first-in-class ST2 inhibitors active in vivo.

Soluble cytokine receptors function as decoy receptors to attenuate cytokine-mediated signaling and modulate downstream cellular responses. Dysregulated overproduction of soluble receptors can be pathological, such as soluble ST2 (sST2), a prognostic biomarker in cardiovascular diseases, ulcerative colitis, and graft-versus-host disease (GVHD). Although intervention using an ST2 antibody improves survival in murine GVHD models, sST2 is a challenging target for drug development because it binds to IL-33 via an extensive interaction interface. Here, we report the discovery of small-molecule ST2 inhibitors through a combination of high-throughput screening and computational analysis. After in vitro and in vivo toxicity assessment, 3 compounds were selected for evaluation in 2 experimental GVHD models. We show that the most effective compound, iST2-1, reduces plasma sST2 levels, alleviates disease symptoms, improves survival, and maintains graft-versus-leukemia activity. Our data suggest that iST2-1 warrants further optimization to develop treatment for inflammatory diseases mediated by sST2.

Anti­IL­39 (IL­23p19/Ebi3) polyclonal antibodies ameliorate autoimmune symptoms in lupus­like mice.

The interleukin (IL)­12 family cytokines have been examined as therapeutic targets in the treatment of several autoimmune diseases. Our previous study showed that a novel IL­12 family cytokine, IL­39 (IL­23p19/Ebi3) mediates inflammation in lupus­like mice. In the present study, the effect of anti­mouse IL­39 polyclonal antibodies on autoimmune symptoms in lupus­like mice was investigated. Rabbit anti­mouse IL­39 polyclonal antibodies were produced by immunization with recombinant mouse IL­39, and purified using protein A chromatography. These antibodies were subsequently used to treat lupus­like mice. Flow cytometry, captured images, ELISA and H&E staining were used to determine the effect of anti­IL­39 polyclonal antibodies on inflammatory cells, autoantibody titers, proteinuria, infiltrating inflammatory cells and the structure of the glomerular region. The anti­IL­39 polyclonal antibodies effectively reduced the numbers of inflammatory cells, splenomegaly, autoantibody titers, proteinuria, infiltrating inflammatory cells, and restored the structure of the glomerular region in MRL/lpr mice. Taken together, these results suggested that anti­IL­39 polyclonal antibodies ameliorated autoimmune symptoms in lupus­like mice. Therefore, IL­39 may be used as a possible target for the treatment of systemic lupus erythematosus.

Virtual screening for inhibitors of the human TSLP:TSLPR interaction.

The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) plays a pivotal role in the pathophysiology of various allergy disorders that are mediated by type 2 helper T cell (Th2) responses, such as asthma and atopic dermatitis. TSLP forms a ternary complex with the TSLP receptor (TSLPR) and the interleukin-7-receptor subunit alpha (IL-7Rα), thereby activating a signaling cascade that culminates in the release of pro-inflammatory mediators. In this study, we conducted an in silico characterization of the TSLP:TSLPR complex to investigate the drugability of this complex. Two commercially available fragment libraries were screened computationally for possible inhibitors and a selection of fragments was subsequently tested in vitro. The screening setup consisted of two orthogonal assays measuring TSLP binding to TSLPR: a BLI-based assay and a biochemical assay based on a TSLP:alkaline phosphatase fusion protein. Four fragments pertaining to diverse chemical classes were identified to reduce TSLP:TSLPR complex formation to less than 75% in millimolar concentrations. We have used unbiased molecular dynamics simulations to develop a Markov state model that characterized the binding pathway of the most interesting compound. This work provides a proof-of-principle for use of fragments in the inhibition of TSLP:TSLPR complexation.

Treg-specific IL-27Rα deletion uncovers a key role for IL-27 in Treg function to control autoimmunity.

Dysregulated Foxp3+ Treg functions result in uncontrolled immune activation and autoimmunity. Therefore, identifying cellular factors modulating Treg functions is an area of great importance. Here, using Treg-specific Il27ra-/- mice, we report that IL-27 signaling in Foxp3+ Tregs is essential for Tregs to control autoimmune inflammation in the central nervous system (CNS). Following experimental autoimmune encephalomyelitis (EAE) induction, Treg-specific Il27ra-/- mice develop more severe EAE. Consistent with the severe disease, the numbers of IFNγ- and IL-17-producing CD4 T cells infiltrating the CNS tissues are greater in these mice. Treg accumulation in the inflamed CNS tissues is not affected by the lack of IL-27 signaling in Tregs, suggesting a functional defect of Il27ra-/- Tregs. IL-10 production by conventional CD4 T cells and their CNS accumulation are rather elevated in Treg-specific Il27ra-/- mice. Analysis with Treg fate-mapping reporter mice further demonstrates that IL-27 signaling in Tregs may control stability of Foxp3 expression. Finally, systemic administration of recombinant IL-27 in Treg-specific Il27ra-/- mice fails to ameliorate the disease even in the presence of IL-27-responsive conventional CD4 T cells. These findings uncover a previously unknown role of IL-27 in regulating Treg function to control autoimmune inflammation.

The Potential Impact of Radix Paeoniae Alba in Embryonic Development of Mice.

Although Radix Paeoniae Alba (RPA) has been ranked as one of the top 6 herbs used frequently to prevent and treat miscarriages clinically, there is no clear evidence regarding its safety in embryonic development. This study aims to evaluate the potential impacts of RPA on embryonic stem cells (ESCs) and pregnant mice. Cytotoxicity assays of the extract were performed in ESCs and 3T3 cells. Pregnant ICR mice were orally treated with RPA extracts at dosages of 0 (G1 group as negative controls), 2, 8 and 32 g/kg/day (G2, G3 and G4 groups) respectively from the gestation day (Gd) 6-15. On Gd 18, there was no significant difference in the IC50 values between ESCs and 3T3 cells (p > 0.05). There was no significant difference in the maternal and fetal evaluations among four groups (p > 0.05). Fetal IL-2, IL-2r, TNF-α, TNF-αr, IL-4, IL-4r, IL-10r, IL-17 and IL-17r of G4 group were significantly lower than G1 group (p < 0.05). In conclusion, RPA at dosage of 32 g/kg/day (16-folds of human daily dosage) did not cause adverse impact in cultured ESCs and pregnant mice. RPA might down-regulate fetal Th1/Th2/Th17 cytokines and receptors maybe beneficial to embryonic survival and development. Copyright © 2017 John Wiley & Sons, Ltd.

Future Prospects of Biologic Therapies for Immunologic Diseases.

This article presents an overview of future uses for biologic therapies in the treatment of immunologic and allergic conditions. Discussion is centered on the use of existing therapies outside of their current indication or on new therapies that are close to approval. This information may help familiarize practicing allergists and immunologists with therapies they may soon encounter in their practice as well as help identify conditions and treatments that will require further study in the near future.

Assessing the New and Emerging Treatments for Atopic Dermatitis.

The newer and emerging treatments for atopic dermatitis (AD) focus on blockade of inflammatory cytokines, especially those that derive from T helper cell type 2 (TH2) and are associated with a pathway of immunoglobulin E (IgE) sensitization. Among the proinflammatory cytokines that have been identified as promising therapeutic targets are chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2), IgE, thymic stromal lymphopoietin (TSLP), and several monoclonal antibodies that block key cytokine pathways in the innate immune response. Two agents that have been studied in phase III clinical trials are the boronbased phosphodiesterase-4 (PDE-4) inhibitor, crisaborole, and dupilumab, an antibody that inhibits the interleukin-4/ IL-13 receptor α chain. Semin Cutan Med Surg 35(supp5):S92-S96.

Orbitopatía de Graves: una enfermedad poco conocida por el oftalmólogo. «El presente y el futuro está en los inhibidores de citoquinas. Cómo y cuándo utilizarlas» / Graves’ ophthalmopathy: A disease little-known by the ophthalmologist. The present and future is in cytokinase inhibitors. How and when to use them

No disponible

Murine allergic rhinitis and nasal Th2 activation are mediated via TSLP- and IL-33-signaling pathways.

Thymic stromal lymphopoietin (TSLP) and IL-33 are epithelium-derived proallergic cytokines that contribute to allergic diseases. Although the involvement of TSLP in allergic rhinitis (AR) is suggested, the exact role of TSLP in AR is poorly understood. Furthermore, the relative contribution of TSLP and IL-33 in nasal allergic responses has not been described. In this study, we examined the roles of TSLP and IL-33 in AR by analyzing acute and chronic AR models. Acute AR mice were intraperitoneally immunized with ragweed, then intranasally challenged with ragweed pollen for four consecutive days. Chronic AR mice were nasally administrated ragweed pollen on consecutive days for 3 weeks. In both models, TSLP receptor (TSLPR)-deficient mice showed defective sneezing responses and reduced serum ragweed-specific IgE levels compared with wild-type (WT) mice. Analyses of bone-marrow chimeric mice demonstrated that hematopoietic cells were responsible for defective sneezing in TSLPR-deficient mice. In addition, FcεRI(+)-cell-specific TSLPR-deficient mice showed partial but significant reduction in sneezing responses. Of note, Th2 activation and nasal eosinophilia were comparable between WT and TSLPR-deficient mice. ST2- and IL-33-deficient mice showed defective Th2 activation and nasal eosinophilia to acute, but not chronic, ragweed exposure. TSLPR and ST2 double-deficient mice showed defective Th2 activation and nasal eosinophilia even after chronic ragweed exposure. These results demonstrate that TSLPR signaling is critical for the early phase response of AR by controlling the IgE-mast-cell/basophil pathway. The IL-33/ST2 pathway is central to nasal Th2 activation during acute allergen exposure, but both TSLPR and ST2 contribute to Th2 responses in chronically allergen-exposed mice.