The Role of Galectins in Asthma Pathophysiology: A Comprehensive Review.

Galectins are a group of ß-galactoside-binding proteins with several roles in immune response, cellular adhesion, and inflammation development. Current evidence suggest that these proteins could play a crucial role in many respiratory diseases such as pulmonary fibrosis, lung cancer, and respiratory infections. From this standpoint, an increasing body of evidence have recognized galectins as potential biomarkers involved in several aspects of asthma pathophysiology. Among them, galectin-3 (Gal-3), galectin-9 (Gal-9), and galectin-10 (Gal-10) are the most extensively studied in human and animal asthma models. These galectins can affect T helper 2 (Th2) and non-Th2 inflammation, mucus production, airway responsiveness, and bronchial remodeling. Nevertheless, while higher Gal-3 and Gal-9 concentrations are associated with a stronger degree of Th-2 phlogosis, Gal-10, which forms Charcot-Leyden Crystals (CLCs), correlates with sputum eosinophilic count, interleukin-5 (IL-5) production, and immunoglobulin E (IgE) secretion. Finally, several galectins have shown potential in clinical response monitoring after inhaled corticosteroids (ICS) and biologic therapies, confirming their potential role as reliable biomarkers in patients with asthma.

IL-13 induced inflammation increases DPP4 abundance but does not enhance MERS-CoV replication in airway epithelia.

BACKGROUND: Chronic pulmonary conditions such as asthma and COPD increase the risk of morbidity and mortality during infection with the Middle East respiratory syndrome coronavirus (MERS-CoV). We hypothesized that individuals with such comorbidities are more susceptible to MERS-CoV infection due to increased expression of its receptor, dipeptidyl peptidase 4 (DPP4). METHODS: We modeled chronic airway disease by treating primary human airway epithelia with the Th2 cytokine IL-13, examining how this impacted DPP4 protein levels along with MERS-CoV entry and replication. RESULTS: IL-13 exposure for 3 days led to increased DPP4 protein abundance, while a 21-day treatment increased DPP4 levels and caused goblet cell metaplasia. Surprisingly, despite this increase in receptor availability, MERS-CoV entry and replication were not significantly impacted by IL-13 treatment. CONCLUSIONS: Our results suggest that increased DPP4 abundance is likely not the primary mechanism leading to increased MERS severity in the setting of Th2 inflammation. Transcriptional profiling analysis highlighted the complexity of IL-13 induced changes in airway epithelia, including altered expression of genes involved in innate immunity, antiviral responses, and maintenance of the extracellular mucus barrier. These data suggest that additional factors likely interact with DPP4 abundance to determine MERS-CoV infection outcomes.

Blood-Based Biomarkers for Eosinophilic Esophagitis and Concomitant Atopic Diseases: A Look into the Potential of Extracellular Vesicles.

Eosinophilic esophagitis (EoE) is a chronic, Th2-inflammatory disease of the esophagus that can severely affect food intake. Currently, diagnosis and assessing response to treatment of EoE is highly invasive and requires endoscopy with esophageal biopsies. Finding non-invasive and accurate biomarkers is important for improving patient well-being. Unfortunately, EoE is usually accompanied by other atopies, which make it difficult to identify specific biomarkers. Providing an update of circulating EoE biomarkers and concomitant atopies is therefore timely. This review summarizes the current knowledge in EoE blood biomarkers and two of its most common comorbidities, bronchial asthma (BA) and atopic dermatitis (AD), focusing on dysregulated proteins, metabolites, and RNAs. It also revises the current knowledge on extracellular vesicles (EVs) as non-invasive biomarkers for BA and AD, and concludes with the potential use of EVs as biomarkers in EoE.

Promotion of a synthetic degradation of activated STAT6 by PARP-1 inhibition: roles of poly(ADP-ribosyl)ation, calpains and autophagy.

BACKGROUND: We reported that PARP-1 regulates genes whose products are crucial for asthma, in part, by controlling STAT6 integrity speculatively through a calpain-dependent mechanism. We wished to decipher the PARP-1/STAT6 relationship in the context of intracellular trafficking and promoter occupancy of the transcription factor on target genes, its integrity in the presence of calpains, and its connection to autophagy. METHODS: This study was conducted using primary splenocytes or fibroblasts derived from wild-type or PARP-1-/- mice and Jurkat T cells to mimic Th2 inflammation. RESULTS: We show that the role for PARP-1 in expression of IL-4-induced genes (e.g. gata-3) in splenocytes did not involve effects on STAT6 phosphorylation or its subcellular trafficking, rather, it influenced its occupancy of gata-3 proximal and distal promoters in the early stages of IL-4 stimulation. At later stages, PARP-1 was crucial for STAT6 integrity as its inhibition, pharmacologically or by gene knockout, compromised the fate of the transcription factor. Calpain-1 appeared to preferentially degrade JAK-phosphorylated-STAT6, which was blocked by calpastatin-mediated inhibition or by genetic knockout in mouse fibroblasts. The STAT6/PARP-1 relationship entailed physical interaction and modification by poly(ADP-ribosyl)ation independently of double-strand-DNA breaks. Poly(ADP-ribosyl)ation protected phosphorylated-STAT6 against calpain-1-mediated degradation. Additionally, our results show that STAT6 is a bonafide substrate for chaperone-mediated autophagy in a selective and calpain-dependent manner in the human Jurkat cell-line. The effects were partially blocked by IL-4 treatment and PARP-1 inhibition. CONCLUSIONS: The results demonstrate that poly(ADP-ribosyl)ation plays a critical role in protecting activated STAT6 during Th2 inflammation, which may be synthetically targeted for degradation by inhibiting PARP-1.

Relevance of TH2 Markers in the Assessment and Therapeutic Management of Severe Allergic Asthma: A Real-Life Perspective.

BACKGROUND: Although blood eosinophils are currently recognized as the main clinical marker of TH2-type inflammation, their relevance in identifying asthma severity remains a matter of debate. METHODS: Our retrospective real-life study on severe asthmatics included in the NEONet Italian database aimed to investigate the relevance of blood eosinophil count and fractional exhaled nitric oxide (FeNO) in the clinical assessment of severe asthma and their role as potential predictors of responsiveness to anti-IgE therapy. The cut-off values chosen were 300 eosinophils/mm3 and FeNO of 30 ppm. RESULTS: We evaluated 132 adult patients. No significant differences were observed between the groups (high and low baseline eosinophil counts) in terms of demographic data, total IgE, lung function, patient-reported outcomes, or nasal comorbidities. The Asthma Control Test score and Asthma Quality of Life Questionnaire scores were poorer in patients with FeNO ≥30 ppb than in patients with FeNO <30 ppb. In the high FeNO subgroup, more frequent hospital admissions and a higher number of working days lost in the previous year were registered. A combined score including both eosinophils and FeNO did not improve the accuracy of the individual parameters. In the high-eosinophil subgroup, the proportion of responders to omalizumab was greater and increased at each follow-up time point. CONCLUSIONS: Our findings show that blood eosinophil count is not an unequivocal marker of asthma severity, whereas a higher FeNO level is associated with more frequent hospital admissions and more working days lost. Blood eosinophils seem to act as a predictor of response to omalizumab.

Type 2/Th2-driven inflammation impairs olfactory sensory neurogenesis in mouse chronic rhinosinusitis model.

BACKGROUND: Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is a chronic inflammatory disease often accompanied by impairment of sense of smell. This symptom has been somewhat overlooked, and its relationship to inflammatory cytokines, tissue compression, neuronal loss, and neurogenesis is still unclear. METHODS: In order to elucidate potential mechanisms leading to CRS in humans, we have established a type 2/T helper type 2 cell (Th2)-mediated allergic CRS mouse model, based on house dust mite (HDM) and Staphylococcus aureus enterotoxin B (SEB) sensitization. The inflammatory status of the olfactory epithelium (OE) was assessed using histology, biochemistry, and transcriptomics. The sense of smell was evaluated by studying olfactory behavior and recording electro-olfactograms (EOGs). RESULTS: After 22 weeks, a typical type 2/Th2-mediated inflammatory profile was obtained, as demonstrated by increased interleukin (IL)-4, IL-5, and IL-13 in the OE. The number of mast cells and eosinophils was increased, and infiltration of these cells into the olfactory mucosa was also observed. In parallel, transcriptomic and histology analyses indicated a decreased number of immature olfactory neurons, possibly due to decreased renewal. However, the number of mature sensory neurons was not affected and neither the EOG nor olfactory behavior was impaired. CONCLUSION: Our mouse model of CRS displayed an allergic response to HDM + SEB administration, including the type 2/Th2 inflammatory profile characteristic of human eosinophilic CRSwNP. Although the sense of smell did not appear to be altered in these conditions, the data reveal the influence of chronic inflammation on olfactory neurogenesis, suggesting that factors unique to humans may be involved in CRSwNP-associated anosmia.

Sulfated non-anticoagulant heparin blocks Th2-induced asthma by modulating the IL-4/signal transducer and activator of transcription 6/Janus kinase 1 pathway.

BACKGROUND: The efficacy of heparins and low-MW-heparins (LMWH) against human asthma has been known for decades. However, the clinical utility of these compounds has been hampered by their anticoagulant properties. Much effort has been put into harnessing the anti-inflammatory properties of LMWH but none have been used as therapy for asthma. Sulfated-non-anticoagulant heparin (S-NACH) is an ultra-LMWH with no systemic anticoagulant effects. OBJECTIVE: The present study explored the potential of S-NACH in blocking allergic asthma and examined the potential mechanism by which it exerts its effects. METHODS: Acute and chronic ovalbumin-based mouse models of asthma, splenocytes, and a lung epithelial cell line were used. Mice were challenged with aerosolized ovalbumin and administered S-NACH or saline 30 min after each ovalbumin challenge. RESULTS: Sulfated-non-anticoagulant heparin administration in mice promoted a robust reduction in airway eosinophilia, mucus production, and airway hyperresponsiveness even after chronic repeated challenges with ovalbumin. Such effects were linked to suppression of Th2 cytokines IL-4/IL-5/IL-13/GM-CSF and ovalbumin-specific IgE without any effect on IFN-γ. S-NACH also reduced lung fibrosis in mice that were chronically-exposed to ovalbumin. These protective effects of S-NACH may be attributed to modulation of the IL-4/JAK1 signal transduction pathway through an inhibition of STAT6 phosphorylation and a subsequent inhibition of GATA-3 and inducible NO synthase expression. The effect of the drug on STAT6 phosphorylation coincided with a reduction in JAK1 phosphorylation upon IL-4 treatment. The protective effects of S-NACH treatment was associated with reduction of the basal expression of the two isoforms of arginase ARG1 and ARG2 in lung epithelial cells. CONCLUSIONS: Our study demonstrates that S-NACH constitutes an opportunity to benefit from the well-known anti-asthma properties of heparins/LMWH while bypassing the risk of bleeding. Our results show, for the first time, that such anti-asthma effects may be associated with reduction of the IL-4/JAK1/STAT6 pathway.

TSLP-activated dendritic cells induce T helper type 2 inflammation in Aspergillus fumigatus keratitis.

Thymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine, which is secreted by epithelial cells under the stimulation of Toll-like receptor (TLR) ligands. Dendritic cells (DCs) which express the thymic stromal lymphopoietin receptor (TSLPR) can be activated by TSLP. Mature DCs can express the OX40 ligand, which has the ability to combine with OX40 on the surface of T cells to stimulate T cell proliferation. TSLP secreted by corneal epithelial cells can engage in the process of T helper type 2 (Th2) inflammation in Aspergillus fumigatus keratitis, but the mechanism remains unclear. We demonstrated that in A. fumigatus-infected corneas, DCs aggregated, matured, and gradually migrated not only from the basement membrane to the corneal epithelium, but also from the corneal limbus to the central cornea. Mature DCs secreted Th2-attracting chemokines, the thymus and activation-regulated chemokine (TARC), and the macrophage-derived chemokine (MDC), encouraging the secretion of TNF-α and Th2 cytokine Interleukin (IL) -4, IL-5, and IL-13. The above processes were all restricted with subconjunctivally injection of TSLP siRNA, while they were strengthened with the injection of rTSLP. We demonstrated that in A. fumigatus keratitis, TSLP, through combination with TSLPR on the surface of DCs, induced DC aggregation, maturation, and migration, and then the mature DCs secreted Th2-attracting chemokines, promoting the secretion of proinflammatory cytokine TNF-α and Th2 cytokines, which finally induced Th2 inflammation.

Emerging drugs for the treatment of perennial allergic rhinitis.

INTRODUCTION: Allergic rhinitis is a worldwide health problem, currently affecting up to 40% of the general population, and characterized by the following symptoms in a variable degree of severity and duration: nasal congestion/obstruction, rhinorrhea, itchy nose and/or eyes, and/or sneezing. General symptoms like fatigue, reduced quality of sleep, impaired concentration and reduced productivity, if left untreated, may significantly affect quality of life. In addition, of being associated to various comorbidities, allergic rhinitis is also an independent risk factor for the development and worsening of asthma. Perennial allergic rhinitis is caused by allergens present around the year. AREAS COVERED: Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines currently recommend a stepwise therapeutic approach that combines patient education with specific allergen avoidance, symptomatic pharmacotherapy and allergen immunotherapy. The available treatment strategies provide suboptimal symptom relief in patients with moderate-to-severe disease who continue to experience symptoms while treated, even on multiple therapies. EXPERT OPINION: New insights into current therapy have been provided with the development of new symptomatic drugs with improved pharmacokinetics and safety. However, the ultimate research goal is beyond symptomatic treatment, and is mainly directed at modifying the immune response to allergens and prevent the progression of allergic rhinitis towards asthma. In this direction, promising advances are expected in the fields of allergen immunotherapy and biological drugs, such as omalizumab. Finally, significant research efforts are also focused on the growing number of new specific molecular targets involved in the Th2 pathway inflammation of allergic diseases.

Chitinase 3-like-1 regulates both visceral fat accumulation and asthma-like Th2 inflammation.

RATIONALE: Obesity, especially truncal obesity, is a risk factor for asthma incidence, prevalence, and severity. Chitinase 3-like-1 (Chi3l1) is an evolutionarily conserved moiety that plays a critical role in antipathogen and Th2 responses. However, the mechanisms that underlie the association between asthma and obesity and the role(s) of Chi3l1 in fat accumulation have not been defined. OBJECTIVES: To determine whether Chi3l1 is regulated by a high-fat diet (HFD) and simultaneously plays an important role(s) in the pathogenesis of asthma and obesity. METHODS: We evaluated the regulation of Chi3l1 by an HFD and Th2 inflammation. We also used genetically modified mice to define the roles of Chi3l1 in white adipose tissue (WAT) accumulation and Th2 inflammation and blockers of sirtuin 1 (Sirt1) to define its roles in these responses. Finally, the human relevance of these findings was assessed with a case-control study involving obese and lean control subjects and those with asthma. MEASUREMENTS AND MAIN RESULTS: These studies demonstrate that an HFD and aeroallergen challenge augment the expression of WAT and pulmonary Chi3l1. Chi3l1 also played a critical role in WAT accumulation and lung Th2 inflammation. In addition, Chi3l1 inhibited Sirt1 expression, and the deficient visceral fat and Th2 responses in Chi3l1 null mice were reversed by Sirt1 inhibition. Finally, serum and sputum Chi3l1 were positively associated with truncal adiposity, and serum Chi3l1 was associated with persistent asthma and low lung function in obese subjects with asthma. CONCLUSIONS: Chi3l1 is induced by an HFD and Th2 inflammation, and simultaneously contributes to the genesis of obesity and asthma.

Th2 cytokines impair innate immune responses to rhinovirus in respiratory epithelial cells.

BACKGROUND: Asthma and other Th2 inflammatory conditions have been associated with increased susceptibility to viral infections. The mechanisms by which Th2 cytokines can influence immune responses to infections are largely unknown. METHODS: We measured the effects of Th2 cytokines (IL-4 and IL-13) on bronchial epithelial cell innate immune antiviral responses by assessing interferon (IFN-ß and IFN-λ1) induction following rhinovirus (RV)-16 infection. We also investigated the modulatory effects of Th2 cytokines on Toll-like receptor 3 (TLR3), interferon-responsive factor 3 (IRF3) and nuclear factor (NF)-kB, that is key molecules and transcription factors involved in the rhinovirus-induced interferon production and inflammatory cascade. Pharmacological and redox modulation of these pathways was also assessed. RESULTS: Th2 cytokines impaired RV-16-induced interferon production, increased rhinovirus replication and impaired TLR3 expression in bronchial epithelial cells. These results were replicated in vivo: we found increased IL-4 mRNA levels in nasal epithelial cells from nasal brushing of atopic rhinitis patients and a parallel reduction in TLR3 expression and increased RV-16 replication compared to nonatopic subjects. Mechanistically, Th2 cytokines impaired RV-16-induced activation of IRF3, but had no effects on RV-16-induced NF-kB activation in bronchial epithelial cell cultures. N-acetylcysteine and phosphoinositide 3-kinase (PI3K) inhibitor restored the inhibitory effects of Th2 cytokines over RV-16-induced activation of IRF3. CONCLUSIONS: IL-4 and IL-13, through inhibition of TLR3 expression and signalling (IRF3), impair immune response to RV-16 infection. These data suggest that Th2 conditions increase susceptibility to infections and identify pharmacological approaches with potential to restore impaired immune response in these conditions.

Adiponectin in Asthma and Obesity: Protective Agent or Risk Factor for More Severe Disease?

PURPOSE: The relationship between asthma and obesity is well established, although the pathophysiological mechanisms linking both diseases remain unknown. Adiponectin is a hormone secreted by adipose cells, plays a role in the modulation of inflammation and may be the key linking these two types of inflammation. METHODS: We conducted a cross-sectional study with asthma with different body mass indices (BMI); the patients were classified as eutrophic, overweight, or obese. We assessed disease control using the GINA consensus, and the levels of adiponectin, C-reactive protein (CRP) and interleukin 33 (IL-33) in each of the patients. RESULTS: We evaluated 75 of the 96 patients eligible for the study, including 25 in each BMI group. The CRP levels were significantly higher in the obese patients compared with both the eutrophic (p = 0.01) and the overweight (p = 0.03) patients. The mean adiponectin level was 21.82 ± 9.93 mg/L for the eutrophic asthmatics, which is a level that was significantly higher than in the overweight (15.31 ± 6.27 mg/L, p = 0.0140) and the obese (16.69 ± 11.45 mg/L, p = 0.0287) patients. The patients with higher adiponectin levels exhibited smaller FEV1 (p = 0.02) and lower FVC (p = 0.003). The IL-33 levels were not different between the groups. CONCLUSIONS: Adiponectin does not protect against the development of inflammation in the setting of asthma and may in fact exacerbate the disease via its anti-TH1 inflammatory effects, allowing for increased TH2 differentiation and a more severe allergic response.

The effects of lebrikizumab in patients with mild asthma following whole lung allergen challenge.

BACKGROUND: Interleukin 13 (IL13) is a T-helper type 2 (Th2) cytokine associated with inflammation and pathology in allergic diseases such as bronchial asthma. We have shown that treatment with lebrikizumab, an anti-IL13 monoclonal antibody, significantly improves prebronchodilator forced expiratory volume in 1 s (FEV(1)) in a subset of subjects with uncontrolled asthma. OBJECTIVE: To evaluate efficacy and safety of lebrikizumab in subjects with mild asthma who underwent bronchial allergen challenge. METHODS: Twenty-nine subjects were randomized 1 : 1-5 mg/kg lebrikizumab (n = 13) or placebo (n = 16) administered subcutaneously every 4 weeks over 12 weeks, a total of four doses. Primary efficacy outcome was late asthmatic response (LAR) at Week 13, defined as area under the curve of FEV1 measured 2-8 h following inhaled allergen challenge. Serum biomarkers were measured to verify IL13 pathway inhibition and identify patients with an increased response to lebrikizumab. RESULTS: At Week 13, the LAR in lebrikizumab subjects was reduced by 48% compared with placebo subjects, although this was not statistically significant (95% confidence interval, -19%, 90%). Exploratory analysis indicated that lebrikizumab-treated subjects with elevated baseline levels of peripheral blood eosinophils, serum IgE, or periostin exhibited a greater reduction in LAR compared with subjects with lower baseline levels of these biomarkers. Lebrikizumab exerted systemic effects on markers of Th2 inflammation, reducing serum immunoglobulin E (IgE), chemokine ligands 13 and 17 by approximately 25% (P < 0.01). Lebrikizumab was well tolerated. CONCLUSION AND CLINICAL RELEVANCE: Lebrikizumab reduced the LAR in subjects with mild asthma. Clinical trial number NCT00781443.

Anti-inflammation of LZTFL1 knockdown in OVA-induced asthmatic mice: Through ERK/GATA3 signaling pathway.

Asthma is a common chronic respiratory disease characterized by Th2-type inflammation in the airways. Leucine zip transcription factor-like 1 (LZTFL1) has been implicated in the regulation of Th2-related factors. The knockdown of LZTFL1 resulted in decreased levels of IL-4, IL-5, and IL-13. We hypothesize that LZTFL1 may have an effect on asthma. We established an acute asthmatic mouse model using the Ovalbumin (OVA) sensitization, and we found that LZTFL1 expression was upregulated in OVA-induced CD4 + T cells. Mice challenged with OVA were administered 5 × 107 TU of lentivirus via tail vein injection. LZTFL1 knockdown reversed the frequency of sneezing and nose rubbing in OVA mice. LZTFL1 knockdown reduced inflammatory cell infiltration, reduced goblet cell numbers, and mitigated collagen deposition in lung tissue. LZTFL1 knockdown decreased the levels of OVA-specific IgE, IL-4, IL-5, and IL-13 in alveolar lavage fluid of asthmatic mice. Furthermore, LZTFL1 knockdown inhibited the aberrant activation of MEK/ERK signaling pathway in asthmatic mice. GATA binding protein 3 (GATA3) is an essential transcription factor in Th2 differentiation. Flow cytometry results revealed that LZTFL1 knockdown reduced the number of GATA3 + CD4 + Th2 cells, while it did not affect the stability of GATA3 mRNA. This may be attributed to ERK signaling which stabilized GATA3 by preventing its ubiquitination and subsequent degradation. In conclusion, LZTFL1 knockdown attenuates inflammation and pathological changes in OVA-induced asthmatic mice through ERK/GATA3 signaling pathway.

Serum inflammatory biomarkers associated with disease severity and response to dupilumab treatment in bullous pemphigoid: A cluster analysis.

BACKGROUND: Dupilumab, a novel therapy targeting the T helper (Th) 2-mediated inflammation, is showing clinical benefits in treating bullous pemphigoid (BP). However, limited research investigated the serum biomarkers that reflect the inflammation alterations throughout the disease course. OBJECTIVES: To explore the changes of the serum inflammatory biomarkers under dupilumab therapy in BP and establish their correlations with disease severity and clinical outcomes. METHODS: This exploratory study evaluated serum samples from 40 patients with BP at baseline, 30 of these patients following 16-week dupilumab therapy, and 20 senior healthy controls. Serum levels of 29 cytokines and chemokines were quantified using the Magnetic Luminex Assay. RESULTS: Two distinct clusters based on serum inflammatory profiles were identified. The first cluster, characterized by elevated levels of inflammatory activation, exhibited worse disease severity and poorer remission outcomes. Following the 16-week dupilumab therapy regimen, a significant suppression of Th2-mediated inflammation in the serum was observed, alongside a relative upregulation of Th1 responses. Patients treated with adjuvant systemic steroids exhibited an enhanced suppression of B cell activating factor compared to those receiving dupilumab alone. Significant correlations were unveiled between Th2 biomarkers and clinical scores, eosinophil counts, and anti-BP180 immunoglobulin G levels. Baseline levels of CCL18, Periostin, interleukin (IL)-6, and IL-16 constitute an optimal combination to distinguish between inflammatory clusters. CONCLUSIONS: Cluster analysis of serum inflammatory biomarkers provided novel insights into the heterogeneity of the inflammation profiles in BP. Baseline levels of CCL18, Periostin, IL-6, IL-16 emerged as effective predictors for disease severity and therapy response to dupilumab.

Airway epithelial-derived exosomes induce acute asthma exacerbation after respiratory syncytial virus infection.

Acute asthma exacerbation refers to the progressive deterioration of asthma symptoms that is always triggered by virus infection represented by respiratory syncytial virus (RSV). After RSV infection, exaggerated Th2-mediated pulmonary inflammation is the critical pathological response of asthmatic patients with acute exacerbation. Significantly, airway epithelial cells, being the primary targets of RSV infection, play a crucial role in controlling the pulmonary inflammatory response by releasing airway epithelial cell-derived exosomes (AEC-Exos), which potentially influence the development of asthma. However, the specific role of AEC-Exos in acute asthma exacerbation after RSV infection remains obscure. The purpose of this study was to determine the distinct function of AEC-Exos in exacerbating acute asthma following RSV infection. Blockade of exosomes by GW reduce the enhanced pulmonary inflammation significantly. Specifically, the enhanced Th2 inflammation was induced by AEC-Exos thorough transportation of hsa-miR-155-5p-Sirtuin 1 (SIRT1) pathway during acute asthma exacerbation. Targeted inhibition of hsa-miR-155-5p blocks the exaggerated Th2 inflammation effectively in mice with acute asthma exacerbation. In summary, our study showed that during acute asthma exacerbation after RSV infection, AEC-Exos promote the enhanced Th2 inflammation through transportation of increased hsa-miR-155-5p, which was mediated partly through SIRT1-mediated pathway. hsa-miR-155-5p is a potential biomarker for early prediction of acute asthma exacerbation.

Diagnosis and management of eosinophilic esophagitis and esophageal food impaction in adults : A position paper issued by the Austrian Society of Gastroenterology and Hepatology (ÖGGH).

This position paper deals with an expert consensus on diagnosis and management of eosinophilic esophagitis and esophageal food impaction issued by the Austrian Eosinophilic Esophagitis Network, a working group under the patronage of the Austrian Society of Gastroenterology and Hepatology (ÖGGH). In need of a standardized approach on the management of EoE, recommendations were made based on international guidelines and landmark studies.

Kaempferol inhibits airway inflammation induced by allergic asthma through NOX4-Mediated autophagy.

BACKGROUND: Kaempferol has important medicinal value in the treatment of asthma. However, its mechanism of action has not been fully understood and needs to be explored and studied. METHODS: A binding activity of kaempferol with nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) was analyzed by molecular docking. Human bronchial epithelial cells (BEAS-2B) were treated with different concentrations (0, 1, 5, 10, 20, 40 µg/mL) of kaempferol to select its suitable concentration. In the transforming growth factor (TGF)-ß1-induced BEAS-2B, cells were treated with 20 µg/mL kaempferol or 20 µM GLX35132 (a NOX4 inhibitor) to analyze its effects on NOX4-mediated autophagy. In the ovalbumin (OVA)-induced mice, 20 mg/kg kaempferol or 3.8 mg/kg GLX351322 administration was performed to analyze the therapeutic effects of kaempferol on NOX4-mediated autophagy. An autophagy activator, rapamycin, was used to confirm the mechanism of kaempferol in treatment of allergic asthma. RESULTS: A good binding of kaempferol to NOX4 (score = -9.2 kcal/mol) was found. In the TGF-ß1-induced BEAS-2B, the NOX4 expression was decreased with kaempferol dose increase. The secretions of IL-25 and IL-33, and the NOX4-mediated autophagy were significantly decreased by kaempferol treatment in the TGF-ß1-induced BEAS-2B. In the OVA-challenged mice, kaempferol treatment improved airway inflammation and remodeling through suppressing NOX4-mediated autophagy. The rapamycin treatment clearly hampered the therapeutic effects of kaempferol in the TGF-ß1-induced cells and OVA-induced mice. CONCLUSIONS: This study identifies kaempferol binds NOX4 to perform its functions in the treatment of allergic asthma, providing an effective therapeutic strategy in the further treatment of asthma.

Pro-tumor Tfh2 cells induce detrimental IgG4 production and PGE2-dependent IgE inhibition in pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis and it is characterized by predominant pro-tumor Th2-type inflammation. T follicular helper (Tfh) cells are relevant immunoregulators in cancer, and often correlate with better survival. How the Th2-skewed microenvironment in PDAC modulates the differentiation of Tfh cells and their immunoregulatory function is unknown. METHODS: We carried out high-dimensional flow cytometry and T-cell receptor- and RNA-sequencing, as well as bioinformatics, immunohistochemistry and in vitro mechanistic studies. FINDINGS: We identified Tfh1-, Tfh2-, and Tfh17-like cell clusters in the blood, tumors and tumor-draining lymph-nodes (TDLNs) of chemo-naïve PDAC patients and showed that high percentages of Tfh2 cells within the tumor tissue and TDLNs correlated with reduced patient survival. Moreover, only Tfh2 cells were highly activated and were reduced in frequency in patients who responded to neoadjuvant chemotherapy. RNA-sequencing analysis of immunoglobulin expression showed that tumor and TDLN samples expressed all immunoglobulin (IGH) isotypes apart from IGHE. Consistent with these findings, Tfh2 cells differentiated in vitro by tumor microenvironment-conditioned dendritic cells promoted the production of anti-inflammatory IgG4 antibodies by co-cultured B cells, dependent on IL-13. Moreover, unexpectedly, Tfh2 cells inhibited the secretion of pro-inflammatory IgE, dependent on prostaglandin E2. INTERPRETATION: Our results indicate that in PDAC, highly activated pro-tumor Tfh2 favor anti-inflammatory IgG4 production, while inhibit pro-inflammatory IgE. Thus, targeting the circuits that drive Tfh2 cells, in combination with chemotherapy, may re-establish beneficial anti-tumor Tfh-B cell interactions and facilitate more effective treatment. FUNDING: Research grants from the Italian Association for Cancer Research (AIRC) IG-19119 to MPP and the AIRC Special Program in Metastatic disease: the key unmet need in oncology, 5 per Mille no. 22737 to CB, MF, CD, MR and MPP; the ERA-NET EuroNanoMed III (a collaborative european grant financed by the Italian Ministry of Health, Italy) project PANIPAC (JTC2018/041) to MPP; the Fondazione Valsecchi to SC.

Food allergy: cause or consequence of pediatric eosinophilic esophagitis? Potential implications of ultraprocessed foods in prevention and management.

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease characterized by eosinophilic infiltration, leading to esophageal dysfunction, inflammation, and fibrotic remodeling. In the last few decades, there has been an increased prevalence of EoE at an alarming rate in the pediatric age. The pathogenesis of EoE is still largely undefined, and this limits the definition of effective strategies for the prevention and management of this condition. EoE is considered a multifactorial disease arising from a negative interaction between environmental factors and genetic background, causing an impaired esophageal epithelial barrier with subsequent abnormal allergen exposure activating type 2 (Th2) inflammation. Food antigens have been suggested as key players in Th2 inflammation in pediatric patients with EoE, but emerging evidence suggests a potential role of other dietary factors, including ultraprocessed foods, as possible triggers for the occurrence of EoE. In this paper, we discuss the potential role of these dietary factors in the development of the disease, and we propose a new approach for the management of pediatric patients with EoE.