Asthma and ulcerative colitis (UC) are chronic inflammatory diseases linked through the "gut-lung axis," but their shared mechanisms remain unclear. This study aims to identify common biomarkers and pathways between asthma and UC using bioinformatics.

Gene expression data for asthma and UC were retrieved from the GEO database, and differentially expressed genes (DEGs) were analyzed. Weighted Gene Coexpression Network Analysis (WGCNA) identified UC-associated gene modules. Shared genes between asthma and UC were derived by intersecting DEGs with UC-associated modules, followed by functional enrichment and protein-protein interaction (PPI) analysis. Machine learning identified hub genes, validated through external datasets using ROC curves, nomograms, and boxplots. Gene Set Enrichment Analysis (GSEA) explored pathway alterations, while immune infiltration patterns were analyzed using the CIBERSORT algorithm. Molecular docking (MD) was performed to predict therapeutic compounds, followed by molecular dynamics simulations on the top-ranked docked complex to assess its binding stability.

A total of 41 shared genes were identified, linked to inflammatory and immune pathways, including TNF, IL-17, and chemokine signaling. Four key hub genes-NOS2, TCN1, CHI3L1, and TIMP1-were validated as diagnostic biomarkers. Immune infiltration analysis showed strong correlations with multiple immune cells. Molecular docking identified several potential therapeutic compounds, with PD 98059, beclomethasone, and isoproterenol validated as promising candidates. The stability of the TIMP1-Beclomethasone complex was determined through molecular dynamics simulations.

This study highlights NOS2, TCN1, CHI3L1, and TIMP1 as potential biomarkers and therapeutic targets for asthma and UC, providing insights into shared mechanisms and new strategies for diagnosis and treatment.

Different types of T helper cells play an important role in disease severity and treatment response in patients with asthma. The potassium channel Kv1.3 is a type of potentially therapeutic target in T-cell-mediated inflammatory diseases.

This study aimed to explore the potential of Kv1.3 as a therapeutic target for asthma and to assess the efficacy of the Kv1.3 inhibitor PAP-1 in the treatment of asthma.

Kv1.3 expression on CD4+T cells was determined using data from public databases. CD4+T cells were isolated from peripheral blood samples obtained from healthy individuals and patients with asthma. The mouse models of OVA-induced asthma and Kv1.3 knockout were established. The underlying mechanism was investigated using mouse splenic CD4+T cells and BEAS-2B cells. OVA-induced asthmatic mice were treated with the Kv1.3 selective blocker PAP-1.

Based on public data, we determined the distribution of Kv1.3 on CD4+T cells, its up-regulation in asthma, and its correlation with Th17/Treg balance. Upregulation of Kv1.3 in CD4+T cells was associated with enhanced activation of these cells and airway inflammation in patients and mice with asthma, accompanied by increased IL-17A levels in alveolar lavage fluid. Conversely, Kv1.3 deficiency significantly attenuated airway inflammation, lowered IL-17A levels in bronchoalveolar lavage fluid, and inhibited airway epithelial-mesenchymal transition in asthmatic mice. Furthermore, treatment with the Kv1.3 selective blocker PAP-1 attenuated inflammation in lung tissues and prevented airway remodeling in OVA-induced asthmatic mice.

Kv1.3 expression on CD4+ T cells was correlated with IL-17A-associated airway inflammation and remodeling in asthma, which may be regarded as a potential diagnostic marker and therapeutic target for asthma.

Based on our study, Kv1.3 expression on CD4+T cells was correlated with IL-17A-associated airway inflammation and remodeling in asthma, which may be regarded as a potential diagnostic marker and therapeutic target for asthma. The treatment with the Kv1.3 selective blocker PAP-1 attenuated inflammation in lung tissues and prevented airway remodeling in OVA-induced asthmatic mice. Our discoveries offer novel perspectives for a better understanding of IL-17A-associated airway remodeling in asthma. The development of drugs targeting Kv1.3 holds application value for IL-17A-associated asthma.

Th17 cells are involved in the pathogenesis of elderly asthma. Bronchial epithelial cells (BECs) can act as antigen-presenting cells, and our previous studies have shown that methyl-CPG binding domain protein 2 (MBD2) in BECs can promote Th17 cell differentiation in asthma. However, the effect of BECs from different age groups (young and old) on Th17 cells remains unclear. In this study, BECs were co-cultured with CD4+ T cells, and it was found that BECs from young mice promoted the biased differentiation of Th2 cells, while BECs from older mice facilitated the biased differentiation of Th17 cells. Interestingly, MBD2 was highly expressed in BECs from older mice compared to BECs from young mice. MBD2 silencing induced inhibition of Th17 cell differentiation, while MBD2 overexpression reversed this change and promoted Th cell differentiation into Th17 cells. Soluble inducible T cell costimulator ligand (sICOSL) is mainly involved in the regulation of T cells after activation. In this study, we found that sICOSL levels were lower in BECs of old mice compared to BECs of young mice. Mechanistically, sICOSL levels increased with MBD2 silencing and decreased with MBD2 overexpression. As expected, the addition of anti-sICOSL antibodies significantly enhanced Th17 cell differentiation and suppressed Th2 cell differentiation, while exogenous sICOSL supplementation promoted Th2 cell differentiation and inhibited Th17 cell differentiation. However, neither anti-sICOSL nor exogenous sICOSL affected the expression of MBD2. Taken together, these results suggest that BECs from older mice regulate Th17 cell differentiation via the MBD2-sICOSL axis. These findings provide new insights into the pathogenesis of Th17-activated asthma in elderly patients.

Effective management of serious respiratory diseases, such as asthma and recalcitrant rhinitis, remains a global challenge. Here, it is shown that induced sputum supernatants (ISS) from patients with asthma contain higher levels of cell-free DNA (cfDNA) compared to that of healthy volunteers. Although cfDNA scavenging strategies have been developed for inflammation modulation in previous studies, this fall short in clinical settings due to the excessive neutrophil extracellular trap (NET) formation, reactive oxygen and nitrogen species (RONS) and bacterial infections in injured airway tissues. Based on this, a multifunctional boron-based 2D nanoplatform B-PM is designed by coating boron nanosheets (B-NS) with polyamidoamine generation 1 (PG1) dendrimer, which can simultaneously target cfDNA, NETs, RONS, and bacteria. The effects of B-PM in promoting mucosal repair, reducing airway inflammation, and mucus production have been demonstrated in model mice, and the therapeutic effect is superior to dexamethasone. Furthermore, flow cytometry with clustering analysis and transcriptome analysis with RNA-sequencing are adopted to comprehensively evaluate the in vivo anti-inflammation therapeutic effects. These findings emphasize the significance of a multi-targeting strategy to modulate dysregulated inflammation and highlight multifunctional boron-based 2D nanoplatforms for the amelioration of respiratory inflammatory diseases.

Steroid-resistant asthma does not respond adequately to corticosteroid treatment. The underlying mechanisms driving corticosteroid resistance remain poorly understood, partly due to the absence of suitable animal models. Identifying the immunomodulatory pathways and mechanisms driving steroid resistance is crucial for developing effective therapies.

In this study, we screened 58 murine strains exposed to house dust mite and identified that the BXD75 strain exhibited neutrophil-skewed, steroid-resistant asthma and elevated Th17 cells. RNA sequencing of lung CD4+ T cells from BXD75 was performed to identify immunomodulatory pathways involved in steroid-resistance. The effects of BTLA agonist treatment were assessed on airway hyperreactivity and lung inflammation.

Transcriptomic analysis revealed increased HVEM expression and decreased BTLA expression, both critical immune regulators associated with stimulatory and inhibitory signaling, respectively. These T cells demonstrated enhanced inflammatory signaling through both canonical and non-canonical NF-κB pathways. BTLA agonist treatment in vivo reduced airway hyperreactivity and lung inflammation, while ex vivo treatment of Th17 cells induced inhibitory signaling via SHP-1, suppressed NF-κB signaling, reduced cell numbers, and lowered IL-17 levels.

Our findings establish BXD75 mice as a model for steroid-resistant asthma and demonstrate that BTLA agonism attenuates airway hyperreactivity and lung inflammation, highlighting it as a potential therapeutic strategy.

Asthma, a chronic respiratory condition that has seen a dramatic rise in prevalence over the past few decades, now affects more than 300 million people globally and imposes a significant burden on healthcare systems. The key pathological features of asthma include inflammation, airway hyperresponsiveness, mucus cell metaplasia, smooth muscle hypertrophy, and subepithelial fibrosis. Cytokines released by lung epithelial cells, stromal cells, and immune cells during asthma are critical to pathological tissue remodeling in asthma. Over the past few decades, researchers have made great strides in understanding key cells involved in asthma and the cytokines that they produce. Epithelial cells as well as many adaptive and innate immune cells are activated by environmental signals to produce cytokines, namely, type 2 cytokines (IL-4, IL-5, IL-13), IFN-γ, IL-17, TGF-β, and multiple IL-6 family members. However, the precise mechanisms through which these cytokines contribute to airway remodeling remain elusive. Additionally, multiple cell types can produce the same cytokines, making it challenging to decipher how specific cell types and cytokines uniquely contribute to asthma pathogenesis. This review highlights recent advances and provides a comprehensive overview of the key cells involved in the production of cytokines and how these cytokines modulate airway remodeling in asthma.

Pediatric obesity-related asthma is characterized by non-atopic T helper 1 (Th1) inflammation and steroid resistance. CDC42 upregulation in CD4 + T cells underlies Th1 inflammation but the CD4 + T cell subtype(s) with CDC42 upregulation and their contribution to steroid resistance are not known. Compared to healthy-weight asthma, obesity-alone and healthy-weight controls, single-cell transcriptomics of obese asthma CD4 + T cells revealed CDC42 upregulation in 3 clusters comprised of naïve and central memory T cells, which differed from the cluster enriched for Th1 responses that was comprised of effector T cells. NR3C1, coding for the glucocorticoid receptor, was downregulated, while genes coding for NLRP3 inflammasome were upregulated, in clusters with CDC42 upregulation and Th1 responses. Conserved genes in these clusters correlated with pulmonary function deficits in obese asthma. These findings suggest that several distinct CD4 + T cell subtypes are programmed in obese asthma for CDC42 upregulation, Th1 inflammation, and steroid resistance, and together contribute to the obese asthma phenotype.

The relationship between diabetes mellitus (DM) and asthma is complex and can impact disease trajectories.

To explore the bidirectional influences between the two conditions on clinical outcomes and disease control.

We systematically reviewed the literature on the relationship between DM and asthma, focusing on their impacts, mechanisms, and therapeutic implications. Various studies were assessed, which investigated the effect of glycemic control on asthma outcomes, lung function, and exacerbations. The study highlighted the role of specific diabetes medications in managing asthma.

The results showed that poor glycemic control in diabetes can exacerbate asthma, increase hospitalizations, and reduce lung function. Conversely, severe asthma, especially in obese individuals, can complicate diabetes management and make glycemic control more difficult. The diabetes-associated mechanisms, such as inflammation, microangiopathy, and oxidative stress, can exacerbate asthma and decrease lung function. Some diabetes medications exhibit anti-inflammatory effects that show promise in mitigating asthma exacerbations.

The complex interrelationship between diabetes and asthma suggests bidirectional influences that affect disease course and outcomes. Inflammation and microvascular complications associated with diabetes may worsen asthma outcomes, while asthma severity, especially in obese individuals, complicates diabetes control. However, the current research has limitations, and more diverse longitudinal studies are required to establish causal relationships and identify effective treatment strategies for individuals with both conditions.

In prednisone-dependent severe asthma, uncontrolled sputum eosinophilia is associated with increased numbers of group 2 innate lymphoid cells (ILC2s). These cells represent a relatively steroid-insensitive source of interleukin-5 (IL-5) and IL-13 and are considered critical drivers of asthma pathology. The abundance of ILC subgroups in severe asthma with neutrophilic or mixed granulocytic (both eosinophilic and neutrophilic) airway inflammation, prone to recurrent infective exacerbations, remains unclear. Here, we found by flow cytometry that sputum ILC3s are increased in severe asthma with intense airway neutrophilia, whereas equivalently raised sputum ILC2s and ILC3s were found in severe asthma with mixed granulocytic inflammation. Unbiased clustering analyses identified an "intermediate-ILC2" population displaying markers of both ILC2s (prostaglandin D2 receptor 2; CRTH2, IL-5, and IL-13) and ILC3s (c-kit and IL-17A) that were most abundant in severe asthma with mixed granulocytic airway inflammation. Intermediate ILC2s correlated with airway neutrophilia and were associated with increased amounts of IL-1β and IL-18 in sputum supernatants. Coculture of sort-purified canonical ILC2s with IL-1β and IL-18 in vitro up-regulated c-kit and IL-17A as well as gene expression profiles related to both type 2 and type 17 inflammatory pathways. Together, we have identified an intermediate-ILC2 phenotype in the airways of individuals with severe mixed granulocytic asthma, representing a candidate therapeutic target for controlling neutrophilic airway inflammation.

Introduction: The shaping of the human intestinal microbiota starts during the intrauterine period and continues through the subsequent stages of extrauterine life. The microbiota plays a significant role in the predisposition and development of immune diseases, as well as various inflammatory processes. Importantly, the proper colonization of the fetal digestive system is influenced by maternal microbiota, the method of pregnancy completion and the further formation of the microbiota. In the subsequent stages of a child's life, breastfeeding, diet and the use of antibiotics influence the state of eubiosis, which determines proper growth and development from the neonatal period to adulthood. The literature data suggest that there is evidence to confirm that the intestinal microbiota of the infant plays an important role in regulating the immune response associated with the development of allergic diseases. However, the identification of specific bacterial species in relation to specific types of reactions in allergic diseases is the basic problem. Background: The main aim of the review was to demonstrate the influence of the microbiota of the mother, fetus and newborn on the functioning of the immune system in the context of allergies and asthma. Methods: We reviewed and thoroughly analyzed the content of over 1000 articles and abstracts between the beginning of June and the end of August 2024. Over 150 articles were selected for the detailed study. Results: The selection was based on the PubMed National Library of Medicine search engine, using selected keywords: "the impact of intestinal microbiota on the development of immune diseases and asthma", "intestinal microbiota and allergic diseases", "the impact of intrauterine microbiota on the development of asthma", "intrauterine microbiota and immune diseases", "intrauterine microbiota and atopic dermatitis", "intrauterine microbiota and food allergies", "maternal microbiota", "fetal microbiota" and "neonatal microbiota". The above relationships constituted the main criteria for including articles in the analysis. Conclusions: In the present review, we showed a relationship between the proper maternal microbiota and the normal functioning of the fetal and neonatal immune system. The state of eubiosis with an adequate amount and diversity of microbiota is essential in preventing the development of immune and allergic diseases. The way the microbiota is shaped, resulting from the health-promoting behavior of pregnant women, the rational conduct of the medical staff and the proper performance of the diagnostic and therapeutic process, is necessary to maintain the health of the mother and the child. Therefore, an appropriate lifestyle, rational antibiotic therapy as well as the way of completing the pregnancy are indispensable in the prevention of the above conditions. At the same time, considering the intestinal microbiota of the newborn in relation to the genera and phyla of bacteria that have a potentially protective effect, it is worth noting that the use of suitable probiotics and prebiotics seems to contribute to the protective effect.

Asthma is a chronic airway inflammatory disease that affects millions globally. Although glucocorticoids are a mainstay of asthma treatment, a subset of patients show resistance to these therapies, resulting in poor disease control and increased morbidity. The complex mechanisms underlying steroid-resistant asthma (SRA) involve Th1 and Th17 lymphocyte activity, neutrophil recruitment, and NLRP3 inflammasome activation. Recent studies provided evidence that innate lymphoid cells type 3 (ILC3s) might be potential therapeutic targets for non-eosinophilic asthma (NEA) and SRA. Like Th17 cells, ILC3s play crucial roles in immune responses, inflammation, and tissue homeostasis, contributing to disease severity and corticosteroid resistance in NEA. Biologics targeting ILC3-related pathways have shown promise in managing Th2-low asthma, suggesting new avenues for SRA treatment. This review aims to explore the risk factors for SRA, discuss the challenges and mechanisms underlying SRA, consolidate current findings on innate lymphoid cells, and elucidate their role in respiratory conditions. We present the latest findings on the involvement of ILC3s in human diseases and explore their potential mechanisms in SRA development. Furthermore, we review emerging therapeutic biologics targeting ILC3-related pathways in managing NEA and SRA. This review highlights current challenges, and emerging therapeutic strategies, and addresses a significant gap in asthma research, with implications for improving the management of steroid-resistant asthma.

IL-17A is a potent proinflammatory cytokine that plays a crucial role in the pathogenesis of various lung diseases. This study focused on the evaluation of the role of IL-17 receptor signaling through one-week intranasal exposure of IL-17A in lung tissues of BALB/c mice. IL-17A triggered inflammatory responses in the mice lungs and led to changes in the morphological alveolar arrangements. Exposure of IL-17A induced redox imbalance by triggering an increase in the level of the pro-oxidants (reactive oxygen species, nitrite and malondialdehyde) and reduction of the levels of antioxidant proteins (glutathione, superoxide dismutase and catalase) in the lung tissue. IL-17A also caused a significant elevation in the levels of proinflammatory cytokines lines including TNF-α, IL-1β and IL-6, in lung tissue as well as in plasma. More interestingly, these changes were accompanied by the alterations in IL-17 receptor downstream signaling through activation of IL-17R-Act1-TRAF6-IKBα-mediated pathway. IL-17A exposure also caused lung tissue injury, recruitment and polarization of immune cells from anti-inflammatory to pro-inflammatory. This study clearly demonstrated the role of IL-17A-induced signaling in worsening lung inflammatory diseases, and hence points towards its emergence as an important therapeutic target to control lung inflammation.

Opportunistic pathogen infection is one of the important inducements for asthma exacerbation. Pseudomonas aeruginosa (PA) is a kind of dominant pathogenic bacteria in the respiratory tract that is associated with severe asthma, but the underlying mechanisms still remains unclear.

To examine the role of PA infection in the bias of the inflammatory endotype in asthma and its effect on the sensitivity to steroid therapy.

An adjusted HDM (House Dust Mite) -induced asthma model with PA inoculation in the airway was utilized to mimic the process of opportunistic PA infection in asthma, focusing on the interaction between bacteria and epithelium. Dexamethasone administration in vivo was used to test the sensitivity to steroid therapy.

It was uncovered that PA could promote the loss of club cells in the necroptosis pattern through cellular CYP450 activation, leading to an imbalance of inflammatory response and steroid insensitivity. Club cell loss results in the activation of cellular E-cadherin/β-catenin axis in the rest of club cells for goblet metaplasia and mucus hypersecretion, as well as epithelial damage and GR downregulation for steroid resistance. For clinical applications, the necroptosis inhibitor Nec-1 can effectively relieve the pathological symptoms of asthma in vivo. Meanwhile, CCSP administration in the airway can regulate the pulmonary inflammation and restore the steroid sensitivity in asthma.

These experiments provide a novel mechanism of concurrent PA infection in asthma through club cell necroptosis and the pathological consequences. Nec-1 treatment and CCSP supplementation may be possible therapeutic strategies for asthma treatment.

Lactotransferrin (LTF) has an immunomodulatory function, and its expression levels are associated with asthma susceptibility.

We sought to investigate LTF messenger RNA (mRNA) expression levels in human bronchial epithelial cells (BECs) as an anti-type 2 (T2) asthma biomarker.

Association analyses between LTF mRNA expression levels in BECs and asthma-related phenotypes were performed in the Severe Asthma Research Program (SARP) cross-sectional (n = 155) and longitudinal (n = 156) cohorts using a generalized linear model. Correlation analyses of mRNA expression levels between LTF and all other genes were performed by Spearman correlation.

Low LTF mRNA expression levels were associated with asthma susceptibility and severity (P < .025), retrospective and prospective asthma exacerbations, and low lung function (P < 8.3 × 10-3). Low LTF mRNA expression levels were associated with high airway T2 inflammation biomarkers (sputum eosinophils and fractional exhaled nitric oxide; P < 8.3 × 10-3) but were not associated with blood eosinophils or total serum IgE. LTF mRNA expression levels were negatively correlated with expression levels of TH2 or asthma-associated genes (POSTN, NOS2, and MUC5AC) and eosinophil-related genes (IL1RL1, CCL26, and IKZF2) and positively correlated with expression levels of TH1 and inflammation genes (IL12A, MUC5B, and CC16) and TH17-driven cytokines or chemokines for neutrophils (CXCL1, CXCL6, and CSF3) (P < 3.5 × 10-6).

Low LTF mRNA expression levels in BECs are associated with asthma susceptibility, severity, and exacerbations through upregulation of airway T2 inflammation. LTF is a potential anti-T2 biomarker, and its expression levels may help determine the balance of eosinophilic and neutrophilic asthma.

Pediatric obesity-related asthma is characterized by non-atopic T helper 1 (Th1) inflammation and steroid resistance. CDC42 upregulation in CD4+T cells underliesTh1 inflammation but the CD4+T cell subtype(s) with CDC42 upregulation and their contribution to steroid resistance are not known. Compared to healthy-weight asthma, obesity-alone and healthy-weight controls, single-cell transcriptomics of obese asthma CD4+T cells revealed CDC42 upregulation in 3 clusters comprised of naïve and central memory T cells, which differed from the cluster enriched for Th1 responses that was comprised of effector T cells. NR3C1, coding for glucocorticoid receptor, was downregulated, while genes coding for NLRP3 inflammasome were upregulated, in clusters with CDC42 upregulation and Th1 responses. Conserved genes in these clusters correlated with pulmonary function deficits in obese asthma. These findings suggest that several distinct CD4+T cell subtypes are programmed in obese asthma for CDC42 upregulation, Th1 inflammation, and steroid resistance, and together contribute to obese asthma phenotype.

CD4+T cells from obese children with asthma are distinctly programmed for non-allergic immune responses, steroid resistance and inflammasome activation, that underlie the obese asthma phenotype.

Asthma comprises one of the most common chronic inflammatory conditions, yet still lacks effective diagnostic markers and treatment targets. To gain deeper insights, we comprehensively analyzed microarray datasets of airway epithelial samples from asthmatic patients and healthy subjects in the Gene Expression Omnibus database using three machine learning algorithms. Our investigation identified a pivotal gene, STEAP4. The expression of STEAP4 in patients with allergic asthma was found to be reduced. Furthermore, it was found to negatively correlate with the severity of the disease and was subsequently validated in asthmatic mice in this study. A ROC analysis of STEAP4 showed the AUC value was greater than 0.75. Functional enrichment analysis of STEAP4 indicated a strong correlation with IL-17, steroid hormone biosynthesis, and ferroptosis signaling pathways. Subsequently, intercellular communication analysis was performed using single-cell RNA sequencing data obtained from airway epithelial cells. The results revealed that samples exhibiting low levels of STEAP4 expression had a richer MIF signaling pathway in comparison to samples with high STEAP4 expression. Through both in vitro and in vivo experiments, we further confirmed the overexpression of STEAP4 in airway epithelial cells resulted in decreased expression of MIF, which in turn caused a decrease in the levels of the cytokines IL-33, IL-25, and IL-4; In contrast, when the STEAP4 was suppressed in airway epithelial cells, there was an upregulation of MIF expression, resulting in elevated levels of the cytokines IL-33, IL-25, and IL-4. These findings suggest that STEAP4 in the airway epithelium reduces allergic asthma Th2-type inflammatory reactions by inhibiting the MIF signaling pathway.

Observational epidemiological studies have indicated a potential association between asthma and sepsis, although the causal relationship between these 2 conditions remains uncertain. To further investigate this relationship, the present study utilized Mendelian randomization (MR) analysis approach to explore the potential links between asthma and various types of sepsis.

In a large-scale genome-wide association study, single nucleotide polymorphisms (SNPs) associated with asthma were selected as instrumental variables. Three methods, including inverse-variance weighted (IVW), MR-Egger regression, and weighted median were used to assess the causal relationship between asthma and sepsis. The odds ratio (OR) and 95% confidence interval (CI) were used as the evaluation metrics for causal relationships, and sensitivity analysis was conducted to assess pleiotropy and instrument validity. Finally, a reverse MR analysis was conducted to investigate whether there is a causal relationship between sepsis and asthma.

We found a positive association between asthma and an increased risk of sepsis (OR=1.18, P＜0.05), streptococcal sepsis (OR=1.23, P=0.04), pneumonia-related sepsis (OR=1.57, P＜0.05), pneumococcal sepsis (OR=1.58, P=0.01), other sepsis (OR=1.15, P＜0.05), and sepsis in intensive care unit (ICU) settings (OR=1.23, P=0.02). Sensitivity analysis showed consistent results without heterogeneity or pleiotropy. The reverse MR analysis reveals no causal relationship between various types of sepsis and asthma.

Our study demonstrates a causal relationship between asthma and different types of sepsis. These findings suggest the importance of healthcare providers paying attention to the potential risk of sepsis in asthma patients and implementing appropriate preventive and intervention measures in a timely manner.

Heightened unfolded protein responses (UPRs) are associated with the risk for asthma, including severe asthma. Treatment-refractory severe asthma manifests a neutrophilic phenotype with T helper (Th)17 responses. However, how UPRs participate in the deregulation of Th17 cells leading to neutrophilic asthma remains elusive. This study found that the UPR sensor IRE1 is induced in the murine lung with fungal asthma and is highly expressed in Th17 cells relative to naive CD4+ T cells. Cytokine (e.g., IL-23) signals induce the IRE1-XBP1s axis in a JAK2-dependent manner. This noncanonical activation of the IRE1-XBP1s pathway promotes UPRs and cytokine secretion by both human and mouse Th17 cells. Ern1 (encoding IRE1) deficiency decreases the expression of endoplasmic reticulum stress factors and impairs the differentiation and cytokine secretion of Th17 cells. Genetic ablation of Ern1 leads to alleviated Th17 responses and airway neutrophilia in a fungal airway inflammation model. Consistently, IL-23 activates the JAK2-IRE1-XBP1s pathway in vivo and enhances Th17 responses and neutrophilic infiltration into the airway. Taken together, our data indicate that IRE1, noncanonically activated by cytokine signals, promotes neutrophilic airway inflammation through the UPR-mediated secretory function of Th17 cells. The findings provide a novel insight into the fundamental understanding of IRE1 in Th17-biased TH2-low asthma.

Asthma is a heterogeneous disease that can be broadly classified into type 2, which is primarily steroid-sensitive and eosinophilic, and non-type 2, which is primarily steroid-resistant and neutrophilic. While the mechanisms leading to the development of molecular-targeted therapies for type 2 asthma are being elucidated, much remains to be learned about non-type 2 asthma. To investigate the role of oxidative stress in refractory allergic airway inflammation, we compared asthma models generated by immunizing wild-type and nuclear factor erythroid-2-related factor 2 (Nrf2)-deficient mice with the house dust mite antigen. Both asthma models had similar levels of airway inflammation and hyperresponsiveness, but the Nrf2-deficient mice had increased oxidative stress and exacerbated neutrophilic airway inflammation compared with the wild-type mice. Type 2 cytokines and the expression of GATA3, a transcription factor that is important for Th2 cell differentiation, had decreased in Nrf2-deficient mice compared with the wild-type mice, whereas helper T (Th) 17 cytokines and the expression of RORγt, which is important for Th17 cell differentiation, had increased. Furthermore, the neutrophilic airway inflammation caused by Nrf2 deficiency was ameliorated by interleukin (IL)-17 neutralization. We have concluded that the disruption of the Nrf2-mediated antioxidant defense system contributed to the induction of Th17 differentiation and exacerbated allergic neutrophilic airway inflammation.

Wildfires are a global concern due to their wide-ranging environmental, economic, and public health impacts. Climate change contributes to an increase in the frequency and intensity of wildfires making smoke exposure a more significant and recurring health concern for individuals with airway diseases. Some of the most prominent effects of wildfire smoke exposure are asthma exacerbations and allergic airway sensitization. Likely due to the delayed recognition of its health impacts in comparison with cigarette smoke and industrial or traffic-related air pollution, research on the composition, the mechanisms of toxicity, and the cellular/molecular pathways involved is poor or non-existent.

This review discusses potential underlying pathological mechanisms of wildfire-smoke-related allergic airway disease and asthma. We focused on major gaps in understanding the role of wildfire smoke composition in the development of airway disease and the known and potential mechanisms involving cellular and molecular players of oxidative injury at the epithelial barrier in airway inflammation. We examine how PM2.5, VOCs, O3, endotoxin, microbes, and toxic gases may affect oxidative stress and inflammation in the respiratory mucosal barrier. We discuss the role of AhR in mediating smoke's effects in alarmin release and IL-17A production and how glucocorticoid responsiveness may be impaired by IL-17A-induced signaling and epigenetic changes leading to steroid-resistant severe airway inflammation.

Effective mitigation of wildfire-smoke-related respiratory health effects would require comprehensive research efforts aimed at a better understanding of the immune regulatory effects of wildfire smoke in respiratory health and disease.

Severe asthma (SA) affects 2% to 5% of asthmatic children. Atopic dermatitis can affect up to 34% of children with SA (cwSA). Atopic dermatitis and asthma share common genetic and immunological features. However, not all children with SA suffer from AD, and it remains unclear whether the overall immune profiles of these children are similar. In this study, seventeen cwSA (9.8 [7.1-13.2] years; seven with and ten without AD) were enrolled. Bronchoalveolar lavage (BAL) and blood samples were collected from these patients. Seventy-three cytokines/chemokines and distinct immune T cell populations were evaluated in blood and BAL. We found that BAL and blood immune profiles of cwSA with and without AD were globally similar. However, specific differences were observed, namely lower frequency of Tc2, Th17 and IL-17-producing mucosal associated invariant T (MAIT-17) cells and higher CD8/CD4 ratio and IL-22 concentrations in BAL and of CCL19 concentrations in plasma from cwSA with AD. Further, in contrast with cwSA without AD, we found a positive correlation between a set of plasma cytokines and almost all cytokines in BAL in cwSA with AD. In conclusion, this study shows the major immune differences between cwSA with and without AD in BAL and blood suggesting that distinct endotypes may be implicated in the inflammatory responses observed in these pediatric patients.

Airway epithelial transcriptome analysis of asthma patients with different severity was used to disentangle the immune infiltration mechanisms affecting asthma exacerbation, which may be advantageous to asthma treatment. Here we introduce various bioinformatics methods and develop two models: an OVA/CFA-induced neutrophil asthma mouse model and an LPS-induced human bronchial epithelial cell damage model. Our objective is to investigate the molecular mechanisms, potential targets, and therapeutic strategies associated with asthma severity. Multiple bioinformatics methods identify meaningful differences in the degree of neutrophil infiltration in asthma patients with different severity. Then, PTPRC, TLR2, MMP9, FCGR3B, TYROBP, CXCR1, S100A12, FPR1, CCR1 and CXCR2 are identified as the hub genes. Furthermore, the mRNA expression of 10 hub genes is determined in vivo and in vitro models. Reperixin is identified as a pivotal drug targeting CXCR1, CXCR2 and MMP9. We further test the potential efficiency of Reperixin in 16HBE cells, and conclude that Reperixin can attenuate LPS-induced cellular damage and inhibit the expression of them. In this study, we successfully identify and validate several neutrophilic signatures and targets associated with asthma severity. Notably, Reperixin displays the ability to target CXCR1, CXCR2, and MMP9, suggesting its potential therapeutic value for managing deteriorating asthma.

Asthma is an inflammatory disease characterized by chronic inflammation in lung tissues and excessive mucus production. High-fat diets have long been assumed to be a potential risk factor for asthma. However, to date, very few direct evidence indicating the involvement of high sucrose intake (HSI) in asthma progression exists. In this study, we investigate the effect of HSI on ovalbumin (OVA)-sensitized allergic asthma mice. We observed that HSI increased the expression of inflammatory genes (IL-1β, IL-6, TNF-α) in adipose tissues and led to reactive oxygen species generation in the liver and lung. In addition, HSI accelerated the TLR4/NF-κB signaling pathway leading to MMP9 activation, which promotes the chemokines and TGF-β secretion in the lungs of OVA-sensitized allergic asthma mice. More importantly, HSI significantly promoted the pathogenic Th2 and Th17 responses. The increase of IL-17A secretion by HSI increased the expression of chemokines (MCP-1, CXCL1, CXCL5, CXCL8). It resulted in eosinophil and mast cell infiltration in the lung and trachea. We also demonstrated that HSI increased mucus hypersecretion, which was validated by increased main mucin protein (MUC5AC) secreted in the lungs. Our findings suggest that HSI exacerbates the development of Th2/Th17-predominant asthma by upregulating the TLR4-mediated NF-κB pathway, leading to excessive MMP9 production.

To establish a juvenile mouse asthma model by postnatal hyperoxia exposure combined with early ovalbumin (OVA) sensitization.

Female C57BL/6J newborn mice were exposed to hyperoxia (95 % O2) from postnatal day-1 (PND1) to PND7; intraperitoneally injected with OVA suspension on PND21, PND28; and stimulated by nebulized inhalation of 1 % OVA from PND36 to PND42. Within 48 h of the last challenge, we observed their activity performance and evaluated airway responsiveness (AHR). All mice were executed at PND44. Female (n = 32) were divided into four groups as follows: room air（RA）+phosphate-buffered saline (PBS) group; O2 (hyperoxia, 95 % O2) + PBS group; RA + OVA group; O2+OVA group. We obtained the serum, bronchoalveolar lavage fluid (BALF), and lung tissues. The Wright-Giemsa staining was performed for leukocyte classification in BALF and HE staining for pathological examination. The levels of IL-2, IL-5, IL-13, IL-17A and IL-10 in BALF and tIgE and sIgE in serum were detected by ELISA.

Compared with OVA sensitization or hyperoxia exposure alone, the mice in the model group (O2+OVA) showed asthma-like symptoms and increased airway hyperreactivity,The levels of IL-5,IL-13 IL-17A were increased in BLAF,and total leukocyte and eosinophil counts were also significant increasesed. The levels of tIgE and sIgE in serum were increased.

Postnatal hyperoxia exposure combined with early OVA sensitization might establish a juvenile mouse asthma model.

Obesity is rapidly becoming a global health problem affecting about 13% of the world's population affecting women and children the most. Recent studies have stated that obese asthmatic subjects suffer from an increased risk of asthma, encounter severe symptoms, respond poorly to anti-asthmatic drugs, and ultimately their quality-of-life decreases. Although, the association between airway hyperresponsiveness (AHR) and obesity is a growing concern among the public due to lifestyle and environmental etiologies, however, the precise mechanism underlying this association is yet to establish. Apart from aiming at the conventional antiasthmatic targets, treatment should be directed towards ameliorating obesity pathogenesis too. Understanding the pathogenesis underlying the association between obesity and AHR is limited, however, a plethora of obesity pathologies have been reported viz., increased pro-inflammatory and decreased anti-inflammatory adipokines, depletion of ROS controller Nrf2/HO-1 axis, NLRP3 associated macrophage polarization, hypertrophy of WAT, and down-regulation of UCP1 in BAT following down-regulated AMPKα and melanocortin pathway that may be correlated with AHR. Increased waist circumference (WC) or central obesity was thought to be related to severe AHR, however, some recent reports suggest body mass index (BMI), not WC tends to exaggerate airway closure in AHR due to some unknown mechanisms. This review aims to co-relate the above-mentioned mechanisms that may explain the copious relation underlying obesity and AHR with the help of published reports. A proper understanding of these mechanisms discussed in this review will ensure an appropriate treatment plan for patients through advanced pharmacological interventions.

Dysregulation of IL-17A is closely associated with airway inflammation and remodeling in severe asthma. However, the molecular mechanisms by which IL-17A is regulated remain unclear. Here we identify epithelial sirtuin 6 (SIRT6) as an epigenetic regulator that governs IL-17A pathogenicity in severe asthma. Mice with airway epithelial cell-specific deletion of Sirt6 are protected against allergen-induced airway inflammation and remodeling via inhibiting IL-17A-mediated inflammatory chemokines and mesenchymal reprogramming. Mechanistically, SIRT6 directly interacts with RORγt and mediates RORγt deacetylation at lysine 192 via its PPXY motifs. SIRT6 promotes RORγt recruitment to the IL-17A gene promoter and enhances its transcription. In severe asthma patients, high expression of SIRT6 positively correlates with airway remodeling and disease severity. SIRT6 inhibitor (OSS_128167) treatment significantly attenuates airway inflammation and remodeling in mice. Collectively, these results uncover a function for SIRT6 in regulating IL-17A pathogenicity in severe asthma, implicating SIRT6 as a potential therapeutic target for severe asthma.

The role of the microbiome in asthma is highlighted, considering its influence on immune responses and its connection to alterations in asthmatic patients. In this context, we review the variables influencing asthma phenotypes from a microbiome perspective and provide insights into the microbiome's role in asthma pathogenesis. Previous cohort studies in patients with asthma have shown that the presence of genera such as Bifidobacterium, Lactobacillus, Faecalibacterium, and Bacteroides in the gut microbiome has been associated with protection against the disease. While, the presence of other genera such as Haemophilus, Streptococcus, Staphylococcus, and Moraxella in the respiratory microbiome has been implicated in asthma pathogenesis, indicating a potential link between microbial dysbiosis and the development of asthma. Furthermore, respiratory infections have been demonstrated to impact the composition of the upper respiratory tract microbiota, increasing susceptibility to bacterial diseases and potentially triggering asthma exacerbations. By understanding the interplay between the microbiome and asthma, valuable insights into disease mechanisms can be gained, potentially leading to the development of novel therapeutic approaches.

Pi-Pa-Run-Fei-Tang (PPRFT) is an empirical TCM prescription for treating asthma. However, the underlying mechanisms of PPRFT in asthma treatment have yet to be elucidated. Recent advances have revealed that some natural components could ameliorate asthma injury by affecting host metabolism. Untargeted metabolomics can be used to better understand the biological mechanisms underlying asthma development and identify early biomarkers that can help advance treatment.

The aim of this study was to verification the efficacy of PPRFT in the treatment of asthma and to preliminarily explore its mechanism.

A mouse asthma model was built by OVA induction. Inflammatory cell in BALF was counted. The level of IL-6, IL-1β, and TNF-α in BALF were measured. The levels of IgE in the serum and EPO, NO, SOD, GSH-Px, and MDA in the lung tissue were measured. Furthermore, pathological damage to the lung tissues was detected to evaluate the protective effects of PPRFT. The serum metabolomic profiles of PPRFT in asthmatic mice were determined by GC-MS. The regulatory effects on mechanism pathways of PPRFT in asthmatic mice were explored via immunohistochemical staining and western blotting analysis.

PPRFT displayed lung-protective effects through decreasing oxidative stress, airway inflammation, and lung tissue damage in OVA-induced mice, which was demonstrated by decreasing inflammatory cell levels, IL-6, IL-1β, and TNF-α levels in BALF, and IgE levels in serum, decreasing EPO, NO, and MDA levels in lung tissue, elevating SOD and GSH-Px levels in lung tissue and lung histopathological changes. In addition, PPRFT could regulate the imbalance in Th17/Treg cell ratios, suppress RORγt, and increase the expression of IL-10 and Foxp3 in the lung. Moreover, PPRFT treatment led to decreased expression of IL-6, p-JAK2/Jak2, p-STAT3/STAT3, IL-17, NF-κB, p-AKT/AKT, and p-PI3K/PI3K. Serum metabolomics analysis revealed that 35 metabolites were significantly different among different groups. Pathway enrichment analysis indicated that 31 pathways were involved. Moreover, correlation analysis and metabolic pathway analysis identified three key metabolic pathways: galactose metabolism; tricarboxylic acid cycle; and glycine, serine, and threonine metabolism.

This research indicated that PPRFT treatment not only attenuates the clinical symptoms of asthma but is also involved in regulating serum metabolism. The anti-asthmatic activity of PPRFT may be associated with the regulatory effects of IL-6/JAK2/STAT3/IL-17 and PI3K/AKT/NF-κB mechanistic pathways.

Interleukin-17A (IL-17A) levels are elevated in patients with asthma. Ferroptosis has been identified as the non-apoptotic cell death type associated with asthma. Data regarding the relation of ferroptosis with asthma and the effect of IL-17A on modulating ferroptosis in asthma remain largely unclear. The present work focused on investigating the role of IL-17A in allergic asthma-related ferroptosis and its associated molecular mechanisms using public datasets, clinical samples, human bronchial epithelial cells, and an allergic asthma mouse model. We found that IL-17A was significantly upregulated within serum in asthma cases. Adding IL-17A significantly increased ferroptosis within human bronchial epithelial cells (BEAS-2B). In ovalbumin (OVA)-induced allergic asthmatic mice, IL-17A regulated and activated lipid peroxidation induced ferroptosis, whereas IL-17A knockdown effectively inhibited ferroptosis in vivo by protection of airway epithelial cells via the xCT-GSH-GPX4 antioxidant system and reduced airway inflammation. Mouse mRNA sequencing results indicated that the tumor necrosis factor (TNF) pathway was the differential KEGG pathway in the OVA group compared to healthy controls and the OVA group compared to the IL-17A knockout OVA group. We further used N-acetylcysteine (TNF inhibitor) to inhibit the TNF signaling pathway, which was found to protect BEAS-2B cells from IL-17A induced lipid peroxidation and ferroptosis damage. Our findings reveal a novel mechanism for the suppression of ferroptosis in airway epithelial cells, which may represent a new strategy for the use of IL-17A inhibitors against allergic asthma.

Immune regulation in chronic rhinosinusitis with nasal polyps (CRSwNP) with a neutrophilic endotype remains unclear. Mucosal-associated invariant T (MAIT) cells are tissue-resident innate T lymphocytes that respond quickly to pathogens and promote chronic mucosal inflammation.

We aimed to investigate the roles of MAIT cells in neutrophilic CRSwNP.

Nasal tissues were obtained from 113 patients with CRSwNP and 29 control subjects. Peripheral and tissue MAIT cells and their subsets were analyzed by flow cytometry. Polyp-derived MAIT cells were analyzed by RNA sequencing to study their effects on neutrophils.

Endotypes of CRSwNP were classified as paucigranulocytic (n = 21), eosinophilic (n = 29), neutrophilic (n = 39), and mixed granulocytic (n = 24). Frequencies of MAIT cells were significantly higher in neutrophilic (3.62%) and mixed granulocytic (3.60%) polyps than in control mucosa (1.78%). MAIT cell percentages positively correlated with local neutrophil counts. MAIT cells were more enriched in tissues than in matched PBMCs. The frequencies of MAIT1 subset or IFN-γ+ MAIT cells were comparable among control tissues and CRSwNP subtypes. The proportions of MAIT17 subset or IL-17A+ MAIT cells were significantly increased in neutrophilic or mixed granulocytic polyps compared with controls. RNA sequencing revealed type 17 and pro-neutrophil profiles in neutrophilic polyp-derived MAIT cells. In patients with neutrophilic CRSwNP, the proportions of MAIT and MAIT17 cells were positively correlated with local proinflammatory cytokines and symptom severity. In vitro experiments demonstrated that neutrophilic polyp-derived MAIT cells promoted neutrophil migration, survival, and activation.

MAIT cells from neutrophilic CRSwNP demonstrate type 17 functional properties and promote neutrophil infiltration in nasal mucosa.

Neutrophils comprise the majority of immune cells in human peripheral circulation, have potent antimicrobial activities, and are clinically significant in their abundance, heterogeneity, and subcellular localization. In the past few years, the role of neutrophils as components of the innate immune response has been studied in numerous ways, and these cells are crucial in fighting infections, autoimmune diseases, and cancer. T-helper 17 (Th17) cells that produce interleukin 17 (IL-17) are critical in fighting infections and maintaining mucosal immune homeostasis, whereas they mediate several autoimmune diseases. Neutrophils affect adaptive immune responses by interacting with adaptive immune cells. In this review, we describe the physiological roles of both Th17 cells and neutrophils and their interactions and briefly describe the pathological processes in which these two cell types participate. We provide a summary of relevant drugs targeting IL-17A and their clinical trials. Here, we highlight the interactions between Th17 cells and neutrophils in diverse pathophysiological situations.

Though asthma is a common and relatively easy to diagnose disease, attempts at primary or secondary prevention, and cure, have been disappointing. The widespread use of inhaled steroids has dramatically improved asthma control but has offered nothing in terms of altering long-term outcomes or reversing airway remodeling and impairment in lung function. The inability to cure asthma is unsurprising given our limited understanding of the factors that contribute to disease initiation and persistence. New data have focused on the airway epithelium as a potentially key factor orchestrating the different stages of asthma. In this review we summarize for the clinician the current evidence on the central role of the airway epithelium in asthma pathogenesis and the factors that may alter epithelial integrity and functionality.

Among preterm infants, the risk of developing asthma is a matter of debate. This review discusses the state of the art of poorly understood prematurity-associated asthma. Impaired pulmonary function is common in children born prematurely. Preterm infants are prone to developing viral respiratory tract infections, bronchiolitis in the first year of life, and recurrent viral wheezing in preschool age. All of these conditions may precede asthma development. We also discuss the role of both atopic sensitization and intestinal microbiome and, consequently, immune maturation. Diet and pollution have been considered to better understand how prematurity could be associated with asthma. Understanding the effect of factors involved in asthma onset may pave the way to improve the prediction of this asthma phenotype.

Childhood asthma is a chronic inflammatory airway disorder that can drive tissue remodeling. Neutrophils are amongst the most prominent inflammatory cells contributing to disease manifestations and may exert a potent role in the progression of inflammation to fibrosis. However, their role in asthma exacerbation is still understudied. Here, we investigate the association between neutrophil extracellular traps (NETs) and lung fibroblasts in childhood asthma pathophysiology using serum samples from pediatric patients during asthma exacerbation. Cell-based assays and NETs/human fetal lung fibroblast co-cultures were deployed. Increased levels of NETs and interleukin (IL)-17A were detected in the sera of children during asthma exacerbation. The in vitro stimulation of control neutrophils using the sera from pediatric patients during asthma exacerbation resulted in IL-17A-enriched NET formation. The subsequent co-incubation of lung fibroblasts with in vitro-generated IL-17A-enriched NETs led fibroblasts to acquire a pre-fibrotic phenotype, as assessed via enhanced CCN2 expression, migratory/healing capacity, and collagen release. These data uncover the important pathogenic role of the NET/IL-17A axis in asthma exacerbation, linking lung inflammation to fibroblast dysfunction and fibrosis.

Treatment-refractory severe asthma manifests a neutrophilic phenotype associated with TH17 responses. Heightened unfolded protein responses (UPRs) are associated with the risk of asthma, including severe asthma. However, how UPRs participate in the deregulation of TH17 cells leading to this type of asthma remains elusive. In this study, we investigated the role of the UPR sensor IRE1 in TH17 cell function and neutrophilic airway inflammation. We found that IRE1 is induced in fungal asthma and is highly expressed in TH17 cells relative to naïve CD4+ T cells. Cytokine (e.g. IL-23) signals induce the IRE1-XBP1s axis in a JAK2-dependent manner. This noncanonical activation of the IRE1-XBP1s pathway promotes UPRs and cytokine secretion by TH17 cells. Ern1 (encoding IRE1)-deficiency decreases the expression of ER stress factors and impairs the differentiation and cytokine secretion of TH17 cells. Genetic ablation of Ern1 leads to alleviated TH17 responses and airway neutrophilia in a Candida albicans asthma model. Consistently, IL-23 activates the JAK2-IRE1-XBP1s pathway in vivo and enhances TH17 responses and neutrophilic infiltration into the airway. Taken together, our data indicate that IRE1, noncanonically activated by cytokine signals, promotes neutrophilic airway inflammation through the UPRmediated secretory function of TH17 cells. The findings provide a novel insight into the fundamental understanding of IRE1 in TH17-biased TH2-low asthma.

A total of 262 million people worldwide suffer from asthma and 461000 people died from it in 2019. Asthma is a disease with different endotypes defined by the granulocytes found in the asthmatic lung. In allergic asthma, the eosinophilic endotype is present, driven by a TH2 response. A TH17 immune response leads to the neutrophil endotype. This often causes uncontrolled asthma and is triggered by pollutants, microbes, and oxidative stress. It has been described that a significant number of patients with eosinophilic asthma develop mixed granulocytic asthma over time. The severity of asthma in the mixed endotype is related to the proportion of neutrophils in the lungs.

In this report, we address the question of how a TH2 response interacts with IL-17A in allergic asthma.

To this end, we used a mouse model to induce allergic asthma followed by an aerosol challenge with ovalbumin. To investigate the role of IL-17A, we administered IL-17A intranasally during the challenge phase.

IL-17A alone did not elicit an immune response, whereas in combination with allergic asthma, it resulted in a shift of the asthmatic endotype from eosinophilic to neutrophilic. TGFβ1 was increased in these lungs compared to asthmatic lungs without IL-17A, as was the expression of the IL-17A receptor subunits IL-17RA and IL-17RC. In cultures with human cells, we also found that IL-17A increased the expression of its receptors only in combination with IL-13. We also found this effect for IL-8, which attracts neutrophils in humans.

The TH2 response increased the sensitivity to IL-17A in a mouse asthma model as well as in human cell lines.