Cannabinoid receptor 2 selective agonist alleviates systemic sclerosis by inhibiting Th2 differentiation through JAK/SOCS3 signaling.

Systemic sclerosis (SSc) poses a significant challenge in autoimmunology, characterized by the development of debilitating fibrosis of skin and internal organs. The pivotal role of dysregulated T cells, notably the skewed polarization toward Th2 cells, has been implicated in the vascular damage and progressive fibrosis observed in SSc. In this study, we explored the underlying mechanisms by which cannabinoid receptor 2 (CB2) highly selective agonist HU-308 restores the imbalance of T cells to alleviate SSc. Using a bleomycin-induced SSc (BLM-SSc) mouse model, we demonstrated that HU-308 effectively attenuates skin and lung fibrosis by specifically activating CB2 on CD4+ T cells to inhibit the polarization of Th2 cells in BLM-SSc mice, which was validated by Cnr2-specific-deficient mice. Different from classical signaling downstream of G protein-coupled receptors (GPCRs), HU-308 facilitates the expression of SOCS3 protein and subsequently impedes the IL2/STAT5 signaling pathway during Th2 differentiation. The deficiency of SOCS3 partially mitigated the impact of HU-308. Analysis of a cohort comprising 80 SSc patients and 82 healthy controls revealed an abnormal elevation in the Th2/Th1 ratio in SSc patients. The proportion of Th2 cells showed a significant positive correlation with mRSS score and positivity of anti-Scl-70. Administration of HU-308 to PBMCs and peripheral CD4+ T cells from SSc patients led to the upregulation of SOCS3, which effectively suppressed the aberrantly activated STAT5 signaling pathway and the proportion of CD4+IL4+ T cells. In conclusion, our findings unveil a novel mechanism by which the CB2 agonist HU-308 ameliorates fibrosis in SSc by targeting and reducing Th2 responses. These insights provide a foundation for future therapeutic approaches in SSc by modulating Th2 responses.

Th2 and metabolic responses to nematodes are independent of prolonged host microbiota abrogation.

Antibiotic treatment can lead to elimination of both pathogenic bacteria and beneficial commensals, as well as to altered host immune responses. Here, we investigated the influence of prolonged antibiotic treatment (Abx) on effector, memory and recall Th2 immune responses during the primary infection, memory phase and secondary infection with the small intestinal nematode Heligmosomoides polygyrus. Abx treatment significantly reduced gut bacterial loads, but neither worm burdens, nor worm fecundity in primary infection were affected, only worm burdens in secondary infection were elevated in Abx treated mice. Abx mice displayed trends for elevated effector and memory Th2 responses during primary infection, but overall frequencies of Th2 cells in the siLP, PEC, mLN and in the spleen were similar between Abx treated and untreated groups. Gata3+ effector and memory Th2 cytokine responses also remained unimpaired by prolonged Abx treatment. Similarly, the energy production and defence mechanisms of the host tissue and the parasite depicted by NAD(P)H fluorescence lifetime imaging (FLIM) did not change by the prolonged use of antibiotics. We show evidence that the host Th2 response to intestinal nematodes, as well as host and parasite metabolic pathways are robust and remain unimpaired by host microbiota abrogation.

Identification of distinct immunophenotypes in chronic pulmonary aspergillosis using cluster analysis.

BACKGROUND: Whether chronic pulmonary aspergillosis (CPA) has different immunophenotypes remains unknown. OBJECTIVE: To identify different CPA immunophenotypes using cluster analysis. METHODS: We used a subject-centred multivariate clustering approach without prior assumptions to identify CPA phenotypes. We retrospectively included the data of treatment-naïve subjects with CPA and excluded subjects with asthma and allergic bronchopulmonary aspergillosis (ABPA). We performed a scalable two-step cluster analysis using the log-likelihood distance measures to identify CPA phenotypes based on the blood immunological profile (total IgE, eosinophil count and Aspergillus-specific IgE and IgG). RESULTS: We included 351 CPA subjects and found two clusters. Cluster 2 (n = 118) had significantly higher serum total IgE, peripheral blood eosinophil count, and serum A. fumigatus-specific IgE and IgG than cluster 1 (n = 233). Cluster 2 subjects had a lower FEV1:FVC ratio on spirometry and were more likely to have a fungal ball (88 [74.6%] vs. 145 (62.2%), p = .023) on the CT thorax than cluster 1. After treatment discontinuation, cluster 2 had a longer median (interquartile range) time to relapse than cluster 1 (11.5 [7.3-27.4] vs. 4 [1.1-8.9] months, p = .005). CONCLUSION: We identified two distinct CPA phenotypes, type-2 dominant and non-type-2, with different clinical and radiological findings and treatment outcomes. Future studies should confirm our findings and investigate different treatment strategies based on CPA phenotypes.

Elements of Th1/Th2 response and disease severity in COVID-19 patients: A short report.

The presence of a complex immune dysregulation syndrome has been established in COVID-19 patients. We aimed to assess Th1/Th2 response in COVID-19 patients and its association with disease severity by performing a prospective cohort study in a tertiary hospital COVID-19 referral center. We report no difference between Th1/Th2 responses between patients with severe and mild disease, except for levels of interleukin-6 (IL-6) and IL-10. Future larger studies should examine lung-specific versus systemic inflammatory responses, as well as, diverse immunotypes driving poor clinical outcomes.

Effects of Oral Exposure to Low-Dose Bisphenol S on Allergic Asthma in Mice.

Bisphenol S (BPS) is increasingly being used as an alternative for bisphenol A; however, its health effects remain unclear. We investigated the effects of oral exposure to low-dose BPS on allergic asthma. C3H/HeJ male mice were intratracheally administered with allergen (ovalbumin (OVA), 1 µg/animal) every 2 weeks from 6 to 11 weeks old. BPS was ingested by drinking water at doses equivalent to 0.04, 0.4, and 4 µg/kg/day. We then examined pulmonary inflammation, airway hyperresponsiveness, serum OVA-specific immunoglobulin (Ig) levels, Th2 cytokine/chemokine production, and mediastinal lymph node (MLN) cell activities. Compared with OVA alone, moderate-dose BPS (BPS-M) with OVA significantly enhanced pulmonary inflammation, airway hyperresponsiveness, and OVA-specific IgE and IgG1. Furthermore, interleukin (IL)-5, IL-13, IL-33, and CCL11/Eotaxin protein levels in the lungs increased. Conversely, these allergic responses were reduced in the high-dose BPS+OVA group. In MLN cells, BPS-M with OVA increased the total cell count and activated antigen-presenting cells including conventional dendritic cell subset (cDC2). After OVA restimulation, cell proliferation and Th2 cytokine production (IL-4, IL-5, and IL-13) in the culture supernatant also increased. Therefore, oral exposure to low-dose BPS may exacerbate allergic asthmatic responses by enhancing Th2-polarized responses and activating the MLN cells.

Ameliorative Effect of Imperatorin on Dermatophagoides pteronyssinus-Induced Allergic Asthma by Suppressing the Th2 Response in Mice.

Imperatorin is a furanocoumarin derivative and an effective ingredient in several Chinese medicinal herbs. It has favorable expectorant, analgesic, and anti-inflammatory effects. In this study, we investigated whether imperatorin has protective effects against Dermatophagoides pteronyssinus (Der p)-induced asthma in mice. Lung and bronchial tissues were histopathologically examined through hematoxylin-eosin staining. The concentrations of immunoglobin E (IgE), IgG1, IgG2a in serum and those of T helper 1 (Th1) and two cytokines and eosinophil-activated chemokines in bronchoalveolar lavage fluid (BALF) were detected using an enzyme immunoassay. Histological examination revealed that imperatorin reduced inflammatory cell infiltration, mucus hypersecretion, and endothelial cell hyperplasia. The examination also indicated that imperatorin could reduce the inflammatory cell count in BALF as well as IgE and IgG1 expression in serum, but IgG2a expression was significantly increased. Imperatorin reduced the production of interleukin (IL)-4, IL-5, and IL-13 by Th2, promoted the production of interferon-γ and IL-12 by Th1, and increased the production of IL-10 in bronchoalveolar lavage fluid. These findings suggest that imperatorin has a considerable anti-inflammatory effect on Der p-induced allergic asthma in mice.

SERPINB10 contributes to asthma by inhibiting the apoptosis of allergenic Th2 cells.

BACKGROUND: Serine peptidase inhibitor, clade B, member 10 (SERPINB10) contributes to allergic inflammation in asthma. However, its role in the T-helper type 2 (Th2) response of allergic asthma is not known. The goal of this study was to unveil the function of SERPINB10 in the Th2 response of allergic asthma and the mechanism by which SERPINB10 affects the viability of Th2 cells. METHODS: Th2 cytokines and serum levels of house dust mite (HDM)-specific IgE in bronchoalveolar lavage fluid were examined by ELISA in an HDM-induced asthma model. The number and apoptosis of Th1 and Th2 cells in mouse lungs were measured by flow cytometry. Naïve CD4 T cells from patients with asthma were cultured under appropriate polarizing conditions to generate Th1 and Th2 cells. SERPINB10 expression in polarized Th1 and Th2 cells was quantified by real-time reverse transcription-quantitative polymerase chain reaction. SERPINB10 expression was knocked down in human CD4 T cells with lentivirus. RESULTS: Knockdown of SERPINB10 expression significantly diminished HDM-induced Th2 cytokine secretion and level of HDM-specific IgE. After HDM exposure, SERPINB10-knockdown mice had diminished numbers of Th2 cells, but similar numbers of Th1 cells, compared with those in negative-control mice. Th2 cells of SERPINB10-knockdown mice were more susceptible to apoptosis than that of control mice. Stimulating T-cell receptors (TCRs) with anti-CD3 antibody caused upregulation of SERPINB10 expression in polarized Th2 cells, but not polarized Th1 cells. Knockdown of SERPINB10 expression resulted in fewer numbers and greater apoptosis of polarized Th2 cells. CONCLUSION: Our results suggest that SERPINB10 may contribute to allergic inflammation and the Th2 response of asthma by inhibiting the apoptosis of Th2 cells.

Parasite-Induced Th2 Polarization-An Unusual Cause of Paediatric Hepatic Abscess.

Liver abscess (LA) is a serious infectious disease, but is relatively rare in the paediatric population, especially in developed countries. Mostly, hepatic abscesses are pyogenic, caused by Staphylococcus aureus, while in extremely rare cases can be caused by parasites, such as Ascaris lumbricoides. Antimicrobial therapy and percutaneous drainage are the treatments of choice, lowering the mortality caused by this infection. We report a case of a 3-year-old girl admitted to the hospital for abdominal pain and a low-grade fever, with abdominal ultrasonography revealing a hepatic lesion. Initial laboratory tests showed moderate anaemia, thrombocytosis, eosinophilia, high inflammatory markers, and normal liver function. A computed tomography scan revealed two liver abscesses located subdiaphragmatically, and a high immunoglobulin E (IgE) value (22,300 U/mL). After excluding other possible etiologies, the patient was tested for parasitic infections. IgE for Ascaris lumbricoides came slightly higher. In addition to empirical antibiotic treatment, the patient received albendazole and made an uneventful recovery, with the full remission of the abscesses and without the need for drainage. In certain cases, parasites such as Ascaris lumbricoides are capable of inducing a T helper 2 (Th2) dominated immune response, predisposing the host to eosinophilia, hyperIgE, and increased susceptibility to bacterial infections. Early diagnosis and treatment in these cases may lead to less invasive therapy options in order to obtain a full recovery. To the best of our knowledge, this is the only reported case in the literature of a paediatric patient with parasite-induced liver abscesses, with extremely high IgE values, minimal symptomatology, that made a fast, full recovery without the need of drainage.

The relationship between human coronaviruses, asthma and allergy-An unresolved dilemma.

Human coronaviruses (HCoVs) such as HCoV-229E or OC43 are responsible for mild upper airway infections, whereas highly pathogenic HCoVs, including SARS-CoV, MERS-CoV and SARS-CoV-2, often evoke acute, heavy pneumonias. They tend to induce immune responses based on interferon and host inflammatory cytokine production and promotion of T1 immune profile. Less is known about their effect on T2-type immunity. Unlike human rhinoviruses (HRV) and Respiratory Syncytial Virus (RSV), HCoVs are not considered as a dominant risk factor of severe exacerbations of asthma, mostly T2-type chronic inflammatory disease. The relationship between coronaviruses and T2-type immunity, especially in asthma and allergy, is not well understood. This review aims to summarize currently available knowledge about the relationship of HCoVs, including novel SARS-CoV-2, with asthma and allergic inflammation.

Differential role of lipoteichoic acids isolated from Staphylococcus aureus and Lactobacillus plantarum on the aggravation and alleviation of atopic dermatitis.

Lipoteichoic acid (LTA), a cell wall component of gram-positive bacteria, up-regulates inflammatory cytokine production through the toll-like receptor 2 (TLR2) signaling pathway, and also contributes to anti-inflammatory responses against immune cells stimulated by lipopolysaccharides. In the current study, we examined the effects of LTAs isolated from Staphylococcus aureus (aLTA) and Lactobacillus plantarum (pLTA) on the aggravation and alleviation of atopic dermatitis (AD). aLTA strongly induced CCL2 production in THP-1 cells. CCL2 was regulated by the TLR2 pathway including the activation of IRAK2, NF-κB and JNK. CCL2 induced Th2 polarization of CD4+T cells through induction of interleukin (IL)-2, -4, and -5 and inhibition of interferon-gamma (IFN-γ). CCL2 levels and immunoglobulin E (IgE) production were increased in aLTA-injected mice. On the other hand, pLTA moderately affected CCL2 production and it inhibited aLTA-mediated CCL2 production. The serum levels of CCL2 and IgE were inhibited by pLTA pre-injection followed by aLTA reinjection, which resulted in the alleviation of irritant contact dermatitis (ICD) symptoms. Our results suggest that S. aureus infection causes an increase in CCL2 production, and may exacerbate atopic dermatitis (AD)-like symptoms through the excessive IgE production. Alternatively, pLTA alleviated AD-like symptoms by inhibiting aLTA-induced CCL2 and IgE production.

Protocatechuic acid supplement alleviates allergic airway inflammation by inhibiting the IL-4Rα-STAT6 and Jagged 1/Jagged2-Notch1/Notch2 pathways in allergic asthmatic mice.

OBJECTIVE AND DESIGN: To clarify the effects of dietary supplementation of protocatechuic acid (PCA) and in-depth mechanisms on allergic asthma in ovalbumin (OVA)-induced mice. MATERIALS: Female BALB/c mice were randomly divided into three groups (n = 10 in each group): control group, OVA-induced allergic asthma group, and OVA plus PCA group. TREATMENT: Dietary supplementation of PCA was achieved by adding 50 mg/kg PCA to AIN 93G diet for 25 days. METHODS: Peripheral blood cells, pulmonary inflammatory cell infiltration, the levels of IL-4, IL-5, and IL-13 in bronchoalveolar lavage fluid (BALF), the mRNA levels of Th2-related genes in the lungs, and the protein expressions of the IL-4Rα-STAT6 and the Jagged1/Jagged2-Notch1/Notch2 signaling pathways were measured. RESULTS: Significantly reduced inflammatory cells infiltration and mucosal hypersecretion in the lung tissues, repaired levels of interleukin IL-4, IL-5, and IL-13 in the BALF, and decreased mRNA expression of IL-4, IL-5, and GATA3 were observed in OVA plus PCA group. Moreover, PCA treatment down-regulated the protein levels of IL-4Rα-STAT6 and Jagged1/Jagged2-Notch1/Notch2 signaling pathways. CONCLUSIONS: Dietary supplement of PCA alleviated allergic asthma partly through suppressing the IL-4Rα-STAT6 and Jagged1/Jagged2-Notch1/Notch2 signaling pathways in mice. Our study provided the theoretic basis of PCA used as functional food in preventing allergic asthma.

The impact of oral exposure to low-dose tris(2-butoxyethyl) phosphate in allergic asthmatic mice.

Tris(2-butoxyethyl) phosphate (TBEP) is a major organophosphorus flame retardant and has been widely increasing as a substitute for brominated flame retardants. TBEP may have adverse effects on human health; however, its impact on immune and allergic responses remains largely uncharacterized. In this study, the effects of low-dose TBEP comparable with the level of actual human exposure to that of human tolerable daily intake on allergic asthmatic mice were explored. Five-week-old C3H/HeJSlc male mice consumed a diet containing approximately 0.02, 0.2 or 2 µg/kg/day TBEP and were intratracheally administrated ovalbumin (OVA) (1 µg/mouse every 2 weeks from 5 to 11 weeks of age). Exposure to 2 µg/kg/day TBEP with OVA tended to enhance allergic pulmonary inflammation and significantly elevated mRNA levels of interleukin-5, eotaxin-1 and estrogen receptor alpha (ERα) compared with OVA alone. In mediastinal lymph nodes (MLNs), TBEP (0.2 or 2 µg/kg/day) with OVA significantly increased in total cell number and promoted conventional dendritic cell activation than OVA alone; MLN cell proliferation by OVA restimulation was also enhanced in these groups. In the bone marrow (BM), TBEP (0.02 or 0.2 µg/kg/day) with OVA resulted in a net decrease in total cell number and fraction of CCR2+ Gr-1+ cells; the fraction of Gr-1+ cells increased. In conclusion, oral exposure to low-dose TBEP levels equivalent to tolerable daily intake may exacerbate allergic pulmonary inflammation by promoting a skewed T-helper 2 cell response, upregulation of ERα and dysregulation of both MLN and BM microenvironments.

The Cellular and Molecular Bases of Allergy, Inflammation and Tissue Fibrosis in Patients with IgG4-related Disease.

IgG4-related disease (IgG4-RD) is a spectrum of complex fibroinflammatory disorder with protean manifestations mimicking malignant neoplasms, infectious or non-infectious inflammatory process. The histopathologic features of IgG4-RD include lymphoplasmacytic infiltration, storiform fibrosis and obliterative phlebitis together with increased in situ infiltration of IgG4 bearing-plasma cells which account for more than 40% of all IgG-producing B cells. IgG4-RD can also be diagnosed based on an elevated serum IgG4 level of more than 110 mg/dL (normal < 86.5 mg/mL in adult) in conjunction with protean clinical manifestations in various organs such as pancreato-hepatobiliary inflammation with/without salivary/lacrimal gland enlargement. In the present review, we briefly discuss the role of genetic predisposition, environmental factors and candidate autoantibodies in the pathogenesis of IgG4-RD. Then, we discuss in detail the immunological paradox of IgG4 antibody, the mechanism of modified Th2 response for IgG4 rather than IgE antibody production and the controversial issues in the allergic reactions of IgG4-RD. Finally, we extensively review the implications of different immune-related cells, cytokines/chemokines/growth factors and Toll-like as well as NOD-like receptors in the pathogenesis of tissue fibro-inflammatory reactions. Our proposals for the future investigations and prospective therapeutic strategies for IgG4-RD are shown in the last part.

The immune response to Hymenolepis nana in mice decreases tumorigenesis induced by 7,12 dimethylbenz-anthracene.

BACKGROUND: Cancer is a high-impact disease throughout the world. A negative correlation has been established between the development of cancer and the Th2 immune response. Infection by helminth parasites is characterized by the induction of a strong and long-lasting Th2 response. The aim of this work was to evaluate the effect of the immune response induced by the infection with the helminth Hymenolepis nana, on the tumorigenesis induced by dimethylbenz-anthracene (DMBA) in mice. METHODOLOGY: Four different groups of 14 female BALB/c mice were formed; Group A, dimethyl sulfoxide (DMSO) (vehicle) was administered cutaneously, Group B infected with H. nana, group C, cutaneously DMBA and finally Group D infected with H. nana and cutaneous DMBA. The tumor load was determined in those animals that developed cancerous lesions. In all groups were determined: serum concentration of IgE, IFNγ, IL-10, IL-5 and malondialdehyde (MDA). The inflammatory infiltrate was analyzed from skin samples and the expression of the main eosinophilic protein and myeloperoxidase was determined. RESULTS: The group previously infected with H. nana had a reduced amount of tumors with smaller size, in comparison to the group that received only DMBA; this reduction was associated with lower levels of IFNγ and IL-10, while levels of IgE, IL-5 and MDA were higher. Further, the number of eosinophils and neutrophils was statistically higher in the animals that were previously infected with the helminth and developed less tumors. CONCLUSION: The immune response induced by H. nana infection is associated with the reduction of tumors probably due to the activity of eosinophils and neutrophils.

Effect of injected dexamethasone on relative cytokine mRNA expression in bronchoalveolar lavage fluid in horses with mild asthma.

BACKGROUND: Mild equine asthma is a common inflammatory airway disease of the horse. The primary treatment of mild equine asthma is corticosteroids. The purpose of this study was to investigate the effects of injected dexamethasone on relative IL-1ß, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p35, IL-17, IL-23, IFN-γ, Eotaxin-2 and TNF-α mRNA expression in bronchoalveolar lavage (BAL) fluid in healthy Thoroughbred horses (n = 6), and those with mild equine asthma (n = 7). RESULTS: Horses with mild equine asthma had a significantly greater bronchoalveolar lavage mast cell percentage than healthy horses both before and after treatment. Mild equine asthma was associated with a 4.95-fold up-regulation of IL-17 (p = 0.026) and a 2.54-fold down-regulation of IL-10 (p = 0.049) compared to healthy horses. TNF-α was down-regulated in response to dexamethasone treatment in both healthy horses (3.03-fold, p = 0.023) and those with mild equine asthma (1.75-fold, p = 0.023). IL-5 was also down-regulated in horses with mild asthma (2.17-fold, p = 0.048). CONCLUSIONS: Horses with mild equine asthma have a lower concentration of IL-10 in BAL fluid than healthy controls which concurs with human asthmatics. The marked up-regulation of IL-17 in horses with mild asthma suggests these horses had a true tendency of "allergic" airway inflammation in response to environmental allergens. Dexamethasone administration exerted anti-inflammatory effects associated with down-regulation of TNF-α in all horses, and decreased levels of IL-5 mRNA expression in horses with mild equine asthma. The inhibition of the Th-2 response, without any alterations to the airway cytology, indicates that maintained exposure to environmental allergens perpetuates airway inflammation.

Metabolic control of type 2 immunity.

Type 2 immune responses play key roles in protection against parasitic worm infections, whole-body metabolic homeostasis, wound healing, and the development of allergies. As a result, there is considerable interest in understanding the pathways that regulate type 2 immunity in order to identify strategies of targeting and controlling these responses. In recent years, it has become increasingly clear that the functional properties of immune cells, including those involved in type 2 immune responses, are dependent on the engagement of specific metabolic pathways such as aerobic glycolysis and fatty acid oxidation (FAO). We here discuss the latest insights in the metabolic regulation of immune cells that initiate type 2 immune responses, such as dendritic cells and innate lymphoid cells, as well as immune cells involved in the effector phase, like T helper 2 (Th2) cells, B cells and alternatively activated macrophages (M2 macrophages). Finally, we consider whether these findings may provide new prospects for the treatment of type 2 immune response-associated diseases.

Tetrahydrocurcumin, a major metabolite of curcumin, ameliorates allergic airway inflammation by attenuating Th2 response and suppressing the IL-4Rα-Jak1-STAT6 and Jagged1/Jagged2 -Notch1/Notch2 pathways in asthmatic mice.

BACKGROUND: Curcumin (Cur), derived from Curcuma species, exhibits anti-inflammatory, antioxidant, and anticancer effects. Although Cur has some beneficial effects on asthma, its clinical application is limited by its low bioavailability. Tetrahydrocurcumin (THC), the major active metabolite of Cur, has multiple biological functions, similarly to Cur, and importantly, it showed enhanced bioavailability in tissues and plasma. However, the effect of THC on asthma has not been reported. OBJECTIVE: The current study sought to investigate the efficacy of dietary THC on allergic asthma compared to that of Cur in an animal model. METHODS: The anti-inflammatory effects of Cur and THC were evaluated in an ovalbumin-induced asthmatic mouse model. The nasal symptoms, pathological alterations of the lung tissues, oxidants and antioxidants, cytokine production, T cell subsets, and Th2-related signalling pathway activity were assessed. RESULTS: Both THC and Cur had beneficial effects on asthmatic mice with regard to nasal symptoms, pathological changes (eosinophils and mucus hyper-production), oxidative stress (malondialdehyde), cytokine production (IL-13), Th17 and cytotoxic T cell subsets, and Th2 signalling pathway (IL-4Rα-Jak1-STAT6 and Jagged1/Jagged2-Notch1/Notch2 axis) activity. THC was more effective than Cur in suppressing tissue eosinophilia, mucus production, and IL-4Rα/Jak1/STAT6 pathway activity. Furthermore, only THC inhibited peripheral eosinophil levels, Th2 cytokines (IL-4 and IL-5), and Th2 cell subsets and enhanced an antioxidant enzyme (glutathione). CONCLUSION AND CLINICAL RELEVANCE: The above results demonstrated for the first time that THC was superior to Cur in modulating allergic asthmatic phenotypes, especially attenuating the Th2 response. THC might be a potentially effective agent for asthma treatment.

Local IL-25 contributes to Th2-biased inflammatory profiles in nasal polyps.

BACKGROUND: IL-25 has been proposed to play a key role in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). This study aimed to evaluate the association of IL-25 with the Th2-biased inflammatory profiles in CRSwNP. METHODS: Nasal polyp (NP) tissues and control uncinate process tissues were collected from 92 patients with CRSwNP, 20 patients with chronic rhinosinusitis without nasal polyps (CRSsNP), and 16 normal control subjects. IL-25 expression was examined using immunohistochemistry and immunofluorescence staining, flow cytometry, RT-qPCR, and ELISA. The inflammatory profiles and clinical characteristics of 2 NP subtypes (IL-25high and IL-25low ) were evaluated, and the effects of IL-25 on Th2 cytokine production in cultured dispersed polyp cells were examined in vitro. RESULTS: The mRNA and protein levels of IL-25 were significantly increased in the polyp tissues compared with the control uncinate process tissues. The IL-25high subtype showed greater computed tomography scores, endoscopic scores, and Th2 response. Exposure to IL-25 activated type 2 innate lymphoid cells and Th2 cells in NP simultaneously which further increased Th2 cytokine production in vitro. CONCLUSIONS: Local IL-25 plays a crucial role in promoting Th2-biased inflammatory profiles in NP and may serve as a promising therapeutic target in CRSwNP patients.

Chitotriosidase inhibits allergic asthmatic airways via regulation of TGF-ß expression and Foxp3+ Treg cells.

BACKGROUND: Chitotriosidase (chitinase 1, Chit1), a major true chitinase in humans, is induced in childhood asthma and has been implicated in the pathogenesis of a variety of inflammatory and tissue remodeling responses. However, the role and the mechanisms that underlie these contributions to the diseases have not been defined. We hypothesized that Chit1 plays a significant role in the pathogenesis of allergic asthma. METHODS: Wild-type and Chit1-deficient mice and cells in culture were used to define the roles of Chit1 in models of allergic adaptive Th2 inflammation. In addition, the levels of sputum Chit1 were evaluated in pediatric asthma patients and compared to control. RESULTS: The levels of sputum Chit1 were significantly increased in the patients with childhood asthma. Mice with Chit1 null mutation demonstrated enhanced allergic Th2 inflammatory and cytokine and IgE responses to OVA or house dust mite allergen sensitization and challenge. However, the expression levels of TGF-ß1 were significantly decreased with a diminished number of Foxp3+ regulatory T cells (Treg) in the lungs of Chit1-/- mice compared to WT controls. In vitro, the absence of Chit1 significantly reduced TGF-ß-stimulated conversion of CD4+ CD25- naïve T cells to CD4+ Foxp3+ Treg cells, suggesting Chit1 is required for optimal effect of TGF-ß1 in Treg cell differentiation. CONCLUSION: Chit1 plays a protective role in the pathogenesis of allergic inflammation and asthmatic airway responses via regulation of TGF-ß expression and Foxp3+ Treg cells.

Increased Th2 activity and diminished skin barrier function cooperate in allergic skin inflammation.

Atopic dermatitis (AD) is a chronic inflammatory skin disease induced by a complex interaction between susceptibility genes encoding skin barrier components and environmental allergen exposure that results in type 2 cytokine production. Although genetic lesions in either component can be risk factors for disease in patients, whether these pathways interact in the development of AD is not clear. To test this, we mated mice with T-cell specific expression of constitutively active Stat6 (Stat6VT) that spontaneously develop allergic skin inflammation with Flaky tail (Ft) mice that have mutations in Flg and Tmem79 genes that each affect skin barrier function. Our results demonstrate that over 90% of the Stat6VT transgenic mice carrying the Ft alleles (Stat6VTxFt-/- ) develop severe atopic dermatitis lesions by 3-5 months of age, compared with only 40% of Stat6VT mice that develop disease by 6-7 months of age. Further, histopathological analysis of skin tissues from Stat6VTxFt-/- mice revealed extensive thickening of the dermis with increased inflammatory infiltrates as compared with Stat6VT mice. Our study suggests that skin barrier defects and altered Th2 responses independently cooperate in the pathogenesis of allergic skin inflammation, similar to effects observed in patients with AD.