Airway Inflammation In Asthma Research Articles

The Therapeutic Potential for Targeting Group 2 Innate Lymphoid Cells in Asthma

T helper type 2 cells (Th2 cells) and group 2 innate lymphoid cells (ILC2s) play an important role in the pathophysiology of asthma, including airway eosinophilic inflammation. ILC2s are activated by epithelial-derived cytokines [interleukin-25 (IL-25), IL-33, and thymic stromal lymphopoietin (TSLP)] from airway epithelial cells, leading to the release of high amounts of type 2 cytokines, such as IL-5 and IL-13. ILC2s induce airway inflammation in an antigen-independent manner, and ILC2s are considered to be involved in the pathogenesis of asthma exacerbation. Furthermore, ILC2 activation might also confer steroid resistance. Many recent studies in humans and mice are increasingly demonstrating that the function of ILC2s is regulated not just by epithelial-derived cytokines but by a variety of cytokines and mediators derived from innate immune cells. Furthermore, the biologics targeting these cytokines and/or their receptors have been shown to reduce asthma exacerbations and improve lung function and quality of life in asthmatics. This article reviews the current treatment landscape for type 2 airway inflammation in asthma and discusses the therapeutic potential for targeting ILC2s.

Gypenoside A from Gynostemma pentaphyllum Attenuates Airway Inflammation and Th2 Cell Activities in a Murine Asthma Model.

Our previous study found that oral administration of Gynostemma pentaphyllum extract can attenuate airway hyperresponsiveness (AHR) and reduce eosinophil infiltration in the lungs of asthmatic mice. Gypenoside A is isolated from G. pentaphyllum. In this study, we investigated whether gypenoside A can effectively reduce asthma in mice. Asthma was induced in BALB/c mice by ovalbumin injection. Asthmatic mice were treated with gypenoside A via intraperitoneal injection to assess airway inflammation, AHR, and immunomodulatory effects. In vitro, gypenoside A reduced inflammatory and oxidative responses in inflammatory tracheal epithelial cells. Experimental results showed that gypenoside A treatment can suppress eosinophil infiltration in the lungs, reduce tracheal goblet cell hyperplasia, and attenuate AHR. Gypenoside A significantly reduced Th2 cytokine expression and also inhibited the expression of inflammatory genes and proteins in the lung and bronchoalveolar lavage fluid. In addition, gypenoside A also significantly inhibited the secretion of inflammatory cytokines and chemokines and reduced oxidative expression in inflammatory tracheal epithelial cells. The experimental results suggested that gypenoside A is a natural compound that can effectively reduce airway inflammation and AHR in asthma, mainly by reducing Th2 cell activation.

Tollip Inhibits IL-33 Release and Inflammation in Influenza A Virus-Infected Mouse Airways

Respiratory influenza A virus (IAV) infection continues to pose significant challenges in healthcare of human diseases including asthma. IAV infection in mice was shown to increase IL-33, a key cytokine in driving airway inflammation in asthma, but how IL-33 is regulated during viral infection remains unclear. We previously found that a genetic mutation in Toll-interacting protein (Tollip) was linked to less airway epithelial Tollip expression, increased neutrophil chemokines, and lower lung function in asthma patients. As Tollip is involved in maintaining mitochondrial function, and mitochondrial stress may contribute to extracellular ATP release and IL-33 secretion, we hypothesized that Tollip downregulates IL-33 secretion via inhibiting ATP release during IAV infection. Wild-type and Tollip knockout (KO) mice were infected with IAV and treated with either an ATP converter apyrase or an IL-33 decoy receptor soluble ST2 (sST2). KO mice significantly lost more body weight and had increased extracellular ATP, IL-33 release, and neutrophilic inflammation. Apyrase treatment reduced extracellular ATP levels, IL-33 release, and neutrophilic inflammation in Tollip KO mice. Excessive lung neutrophilic inflammation in IAV-infected Tollip KO mice was reduced by sST2, which was coupled with less IL-33 release. Our data suggest that Tollip inhibits IAV infection, potentially by inhibiting extracellular ATP release and reducing IL-33 activation and lung inflammation. In addition, sST2 may serve as a potential therapeutic approach to mitigate respiratory viral infection in human subjects with Tollip deficiency.

Muscarinic Receptor Antagonism and Allergen Induced Airway Responses in Allergic Asthma: A Scoping Review

The purpose of this scoping review was to identify existing clinical and basic science knowledge surrounding the effect of muscarinic receptor antagonism on allergen-induced airway responses to inform future clinical research in this area. Multiple advanced searches were performed using the National Library of Medicine PubMed search engine. Each search began with two terms; for example, "atropine and asthma" or "tiotropium and airway inflammation". Results were then further refined to include terms such as "allergen" or "ovalbumin (OVA)". Abstracts of refined searches were reviewed for relevance to allergic asthma and allergen-induced airway responses including the early and late asthmatic responses, airway inflammation and tissue remodelling. There was no restriction regarding publication date. Reference lists of selected papers were also reviewed for relevant publications. Nine human clinical trial publications and fourteen animal model publications were identified. In humans, single dose atropine (n=4), ipratropium (n=4) or oxitropium (n=1) administered pre-challenge produced equivocal effects on allergen-induced early asthmatic responses as reported but favored inhibition in eight of nine studies after re-analyses. Animal model investigations (n=14) showed mostly favorable results, especially with respect to airway inflammation and tissue remodelling, although two studies were negative, and one study showed a worsening in allergen induced airway inflammation following muscarinic receptor antagonism. Existing human and animal model data suggest muscarinic receptor antagonism may be beneficial in preventing allergen induced airway responses in those with allergic asthma. Additional human research utilizing current standardized methodologies is required.

Increased Oxidative Stress in Asthma-Relation to Inflammatory Blood and Lung Biomarkers and Airway Remodeling Indices.

Airway inflammation in asthma is related to increased reactive oxygen species generation, potentially leading to tissue injury and subsequent airway remodeling. We evaluated oxidative stress in peripheral blood from asthmatic subjects (n = 74) and matched controls (n = 65), using recently developed real-time monitoring of the protein hydroperoxide (HP) formation by the coumarin boronic acid (CBA) assay. We also investigated the relation of the systemic oxidative stress response in asthma to disease severity, lung function, airway remodeling indices (lung computed tomography and histology), and blood and bronchoalveolar lavage fluid (BAL) inflammatory biomarkers. We documented enhanced systemic oxidative stress in asthma, reflected by 35% faster and 58% higher cumulative fluorescent product generation in the CBA assay (p < 0.001 for both). The dynamics of HP generation correlated inversely with lung function but not with asthma severity or histological measures of airway remodeling. HP generation was associated positively with inflammatory indices in the blood (e.g., C-reactive protein) and BAL (e.g., interleukin [IL]-6, IL-12p70, and neutrophil count). Bronchial obstruction, thicker airway walls, increased BAL IL-6, and citrullinated histone 3 in systemic circulation independently determined increased HP formation. In conclusion, a real-time CBA assay showed increased systemic HP generation in asthma. In addition, it was associated with inflammatory biomarkers, suggesting that proper disease control can also lead to a decrease in oxidative stress.

Role of Obesity in Inflammation and Remodeling of Asthmatic Airway.

Obesity is considered as an important risk factor for the onset of asthma and plays a key role in enhancing the disease’s severity. Obese asthmatic individuals represent a distinct phenotype of asthma that is associated with additional symptoms, more severe exacerbation, decreased response to standard medication, and poor quality of life. Obesity impairs the function of the lung airway in asthmatic individuals, leading to increased inflammation and severe remodeling of the bronchus; however, the molecular events that trigger such changes are not completely understood. In this manuscript, we review the current findings from studies that focused on understanding the role of obesity in modulating the functions of airway cells, including lung immune cells, epithelial cells, smooth muscle cells, and fibroblasts, leading to airway inflammation and remodeling. Finally, the review sheds light on the current knowledge of different therapeutic approaches for treating obese asthmatic individuals. Given the fact that the prevalence of asthma and obesity has been increasing rapidly in recent years, it is necessary to understand the molecular mechanisms that play a role in the disease pathophysiology of obese asthmatic individuals for developing novel therapies.

Iristectorigenin A exerts novel protective properties against airway inflammation and mucus hypersecretion in OVA-induced asthmatic mice: Iristectorigenin A ameliorates asthma phenotype

BackgroundDespite the substantial amount of efforts made to reduce morbidity and improve respiratory management, asthma control remained a major challenge for severe patients. Plant isoflavones, one of the most estrogenic compounds, are considered a potential alternative therapy for asthma. Iristectorigenin A, a naturally occurring isoflavone, is extracted from a variety of medical plants and its biological activity has not been reported previously. PurposeIn present study, we aim to reveal the potential therapeutic role of Iristectorigenin A against acute asthmatic mice. Study designWe established ovalbumin (OVA) induced asthmatic murine model and orally administrated Iristectorigenin A at concentration of 5 and 10 mg/kg and dexamethasone as a positive control substance. MethodsAsthmatic murine model was established with OVA sensitization and challenge. Lung function was assessed with FinePoint Ventilation system recording lung resistance (RI) and lung compliance (Cydn). White cells were sorted and counted in BALF. Histopathological assessment was conducted by H&E, PAS, and Masson's trichrome staining on paraffin embedded lung tissues. BALF content of IL-4, IL-5, IL-33, IL-13, INF-γ, IL-9 and serum IgE, IgG1 were measured using ELISA kit. Expression levels of mRNAs associated with inflammatory cytokines and goblet cell metaplasia were evaluated via quantitative RT-PCR. Protein expression levels of FOXA3, MUC5AC, SPDEF were estimated by immunohistochemistry on lung tissue, while NOTCH1 and NOTCH2 expressions were evaluated by western blotting analysis. ResultsIristectorigenin A resulted in improved airway hyperresponsiveness (AHR) mirrored by decreased RI and increased Cydn. With Iristectorigenin A, we also observed reduced number of BALF leukocytes, improved inflammatory cell infiltration in lung tissue, decreased content of BALF IL-4, IL-5, IL-33, but not IL-13, INF-γ, IL-9, and their mRNA levels, along with decreased levels of OVA-specific IgE, IgG1 in asthmatic mice. Additionally, Iristectorigenin A exhibited significant therapeutic potential on attenuating mucus production reflected by mitigated FOXA3 and MUC5AC immunostaining on the airway epithelium, as well as decreased mRNAs associated with goblet cell metaplasia. At last, a decrease in elevated expression level of NOTCH2, but not NOTCH1, in asthmatic mice lung tissue was observed by western blotting analysis. ConclusionOur study provides strong evidence that Iristectorigenin A can be potential therapeutic agent ameliorating airway inflammation and mucus hypersecretion in allergic asthma. This is a first research reported the potential of Iristectorigenin A as an alternative therapeutic agent.

MiR-146a-5p Attenuates Allergic Airway Inflammation by Inhibiting the NLRP3 Inflammasome Activation in Macrophages

Objective: Asthma is a common inflammatory respiratory disease with increasing incidence worldwide. This study aimed to investigate the mechanism of miR-146a-5p in reducing allergic airway inflammation by inhibiting NLRP3 inflammasome activation in macrophages. Methods: Allergic mouse models were established by ovalbumin stimulation, and mice were treated with miR-146a-5p agomir and oe-TIRAP 3 h before OVA stimulation. The pathological changes of lung tissues were observed by hematoxylin-eosin staining. The airway hyperresponsiveness of mice were examined. The miR-146a-5p level was detected by RT-qPCR. The inflammatory cytokines (IL-18/TNF-α) and anti-inflammatory cytokine IL-10 levels in bronchoalveolar lavage fluid and serum IgE levels were examined by ELISA. Airway inflammation in mice was detected after miR-146a-5p overexpression. The levels of NLRP3/ASC/caspase1 proteins and macrophage M1/M2 surface markers in mouse lung tissues were examined using immunohistochemistry, Western blot, and flow cytometry. The targeting relationship between miR-146a-5p and TIRAP was verified by dual-luciferase assay. The p65 levels in the cytoplasm/nucleus of mouse lung tissue were measured. Results: miR-146a-5p was downregulated in the lung tissues of allergic mice, and miR-146a-5p overexpression alleviated airway inflammation in asthmatic mice. miR-146a-5p suppressed NLRP3 inflammasome activation in macrophages of allergic mice, reduced NLRP3/ASC/caspase1 protein levels in lung tissues, blocked M1 polarization, and promoted M2 polarization. miR-146a-5p targeted TIRAP. TIRAP overexpression partially reversed the promoting effect of miR-146a-5p on M2 polarization. miR-146a-5p can inhibit the activation of the TIRAP/NF-κB pathway. Conclusion: miR-146a-5p inhibited NLRP3 inflammasome activation in macrophages in the lung tissue of allergic mice, prevented pro-inflammatory phenotype M1 polarization, and promoted anti-inflammatory phenotype M2 polarization by targeting the TIRAP/NF-κB pathway, thus alleviating airway inflammation in allergic asthma.

MicroRNA-182-5p Attenuates Asthmatic Airway Inflammation by Targeting NOX4.

Bronchial asthma is characterized by chronic airway inflammation, airway hyperresponsiveness, and airway remodeling. MicroRNA (miRNA) has recently been implicated in the pathogenesis of asthma. However, the mechanisms of different miRNAs in asthma are complicated, and the mechanism of miRNA-182-5p in asthma is still unclear. Here, we aim to explore the mechanism of miRNA182-5p in asthma-related airway inflammation. Ovalbumin (OVA)-induced asthma model was established. MiRNA Microarray Analysis was performed to analyze the differentially expressed miRNAs in the asthma model. We found that the expression of miRNA-182-5p was significantly decreased in OVA-induced asthma. In vitro, IL-13 stimulation of BEAS-2B cells resulted in a significant up-regulation of NOX4 (nicotinamide adenine dinucleotide phosphate oxidase 4), accompanied by mitochondrial damage-induced apoptosis, NLRP3 (NOD-like receptor family pyrin domain-containing 3)/IL-1β activation, and reduced miRNA-182-5p. In contrast, overexpression of miRNA-182-5p significantly inhibited epithelial cell apoptosis and NLRP3/IL-1β activation. In addition, we found that miRNA-182-5p could bind to the 3’ untranscripted region of NOX4 mRNA and inhibit epithelial cell inflammation by reducing oxidative stress and mitochondrial damage. In vivo, miRNA-182-5p agomir treatment significantly reduced the percentage of eosinophils in bronchoalveolar lavage fluid, and down-regulated Th2 inflammatory factors, including IL-4, IL-5, and OVA induced IL-13. Meanwhile, miRNA-182-5p agomir reduced the peribronchial inflammatory cell infiltration, goblet cell proliferation and collagen deposition. In summary, targeting miRNA-182-5p may provide a new strategy for the treatment of asthma.

Nontypeable Haemophilusinfluenzae infection of pulmonary macrophages drives neutrophilic inflammation in severe asthma.

Nontypeable Haemophilus influenzae (NTHi) is a respiratory tract pathobiont that chronically colonizes the airways of asthma patients and is associated with severe, neutrophilic disease phenotypes. The mechanism of NTHi airway persistence is not well understood, but accumulating evidence suggests NTHi can persist within host airway immune cells such as macrophages. We hypothesized that NTHi infection of pulmonary macrophages drives neutrophilic inflammation in severe asthma. Bronchoalveolar lavage (BAL) samples from 25 severe asthma patients were assessed by fluorescence in situ hybridisation to quantify NTHi presence. Weighted gene correlation network analysis (WGCNA) was performed on RNASeq data from NTHi-infected monocyte-derived macrophages to identify transcriptomic networks associated with NTHi infection. NTHi was detected in 56% of BAL samples (NTHi+) and was associated with longer asthma duration (34 vs 22.5 years, p=.0436) and higher sputum neutrophil proportion (67% vs 25%, p=.0462). WGCNA identified a transcriptomic network of immune-related macrophage genes significantly associated with NTHi infection, including upregulation of T17 inflammatory mediators and neutrophil chemoattractants IL1B, IL8, IL23 and CCL20 (all p < .05). Macrophage network genes SGPP2 (p=.0221), IL1B (p=.0014) and GBP1 (p=.0477) were more highly expressed in NTHi+ BAL and moderately correlated with asthma duration (IL1B; rho=0.41, p=.041) and lower prebronchodilator FEV1/FVC% (GBP1; rho=-0.43, p=.046 and IL1B; rho=-0.42, p=.055). NTHi persistence with pulmonary macrophages may contribute to chronic airway inflammation and T17 responses in severe asthma, which can lead to decreased lung function and reduced steroid responsiveness. Identifying therapeutic strategies to reduce the burden of NTHi in asthma could improve patient outcomes.

Blockade of NLRP3/Caspase-1/IL-1β Regulated Th17/Treg Immune Imbalance and Attenuated the Neutrophilic Airway Inflammation in an Ovalbumin-Induced Murine Model of Asthma

Asthma is a heterogeneous inflammatory disorder of the airways, and multiple studies have addressed the vital role of the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3)/caspase-1/interleukin-1β (IL-1β) pathway in asthma, but its impact on ovalbumin- (OVA-) induced neutrophilic asthma remains unclear. Here, we explored this pathway's effect on airway inflammation in neutrophilic asthma to clarify whether blocking this signaling could alleviate asthmatic airway inflammation. Using an established OVA-induced neutrophilic asthma mouse model, we provided asthmatic mice with a highly selective NLRP3 inhibitor, MCC950, and a specific caspase-1 inhibitor, Ac-YVAD-cmk. Our results indicated that asthmatic mice exhibited increased airway hyperresponsiveness, neutrophil infiltration, and airway mucus hypersecretion, upregulated retinoid-related orphan receptor-γt (RORγt) mRNA expression, and downregulated fork head box p3 (Foxp3) mRNA expression, which was concurrent with NLRP3 inflammasome activation and upregulation of caspase-1, IL-1β, and IL-18 expression in lung. Treatment of NLRP3 inflammasome inhibitors significantly attenuated airway hyperresponsiveness, airway inflammation, and reversed T helper 17 (Th17)/regulatory T (Treg) cell imbalance in asthmatic mice. We propose that the NLRP3/caspase-1/IL-1β pathway plays an important role in the pathological process of neutrophilic asthma and provides evidence that blocking this pathway could potentially be a treatment strategy to ameliorate airway inflammation in asthma after validation with future experimental and clinical studies.

GPR43 signaling in lung eosinophils suppresses neutrophilic airway inflammation in asthma

Abstract Asthma is caused by chronic inflammation in airways. It typically manifests type 2 immune activation and eosinophilia, while more severe, steroid-resistant asthma involves additional activation of Th17 cells and neutrophils. Even though pathogenic roles of eosinophils in asthma have been extensively studied, regulatory mechanisms curving down their overactivation are not well known. We found that eosinophils in asthmatic lung highly upregulate expression of GPR43, a receptor for short-chain fatty acid mediating various anti-inflammatory responses. In eosinophil-specific GPR43-deficient (GPR43ΔEOS) mice, asthma induction by Ova/alum or house dust mite extracts resulted in increased activation of Th17 cells and neutrophils in the lung compared to wild type mice. Consequently, GPR43ΔEOS mice showed more severe lung pathology and disease phenotype. Moreover, we identified a distinct Siglec-F+ neutrophil subset is enriched in GPR43ΔEOS mice by scRNA-seq analysis of the asthmatic lungs. Siglec-F+ neutrophils were recently shown to mediate Th17 cell activation and aggravation of asthma in vivo. We also found that Siglec-F+ neutrophils promote in vitro Th17 differentiation. Co-culture experiments of lung eosinophils and bone marrow neutrophils revealed that GPR43-deficient eosinophils directly mediate conversion of Siglec-F-neutrophils into Siglec-F+ neutrophils via GM-CSF secretion. Combined, our results demonstrate that GPR43 signaling in lung eosinophils prevents generation of Siglec-F+ neutrophils and Th17 cell activation, thereby suppressing severe asthma pathology.

Androgen receptor signaling decreases glutaminolysis in Th17 cells to reduce airway inflammation in asthma

Abstract Women have higher rates of severe asthma compared to men. Severe asthma has increased Th2-mediated eosinophilic and/or Th17-mediated neutrophilic airway inflammation. We showed androgens, signaling through the androgen receptor (AR), decreased Th2- and Th17-mediated airway inflammation, and that Th17 and Th2 rely on glutaminolysis during allergic airway inflammation. Therefore, we hypothesized that AR signaling decreases glutaminolysis in Th2 and Th17 cells, resulting in decreased airway inflammation. Th2 and Th17 were differentiated in vitro from wild-type male and ArTfm male mice, with a nonfunctional AR. Mitochondrial metabolism and glycolysis were determined by measuring oxygen consumption rate (OCR), reactive oxygen species (ROS), and the extracellular acidification rate (ECAR). In Th17 cells, AR signaling decreased OCR, while increasing mitochondrial ROS, suggesting decreased glutaminolysis. Further, both 5α-DHT (0.1nM) and CB839 (a glutaminase inhibitor, 0.5μM) reduced OCR in Th17 cells from male mice. AR signaling had no effect on ECAR in Th17 cells or OCR and ECAR in Th2 cells. To induce eosinophilic and neutrophilic airway inflammation, house dust mite (HDM) was intranasally administered to ArfloxedCD4-Cre and Arfloxed male mice and markers of glycolysis and glutaminolysis were determined by flow cytometry. AR signaling decreased airway neutrophils, the number of Th17 lung cells, and GLUD1, a glutaminolysis marker, expression in T cells, but had no effect on eosinophils or Th2 cells. Combined, these data showed that AR signaling decreased glutaminolysis in Th17, but not Th2, cells. Understanding these pathways may provide new potential therapeutic targets in women with difficult-to-treat asthma. Supported by grants from NIH (R01 HL12254, R01 HL136664, T32 GM007347)

Junction adhesion molecule‐A is involved in asthma through JNK and ERK pathway

BackgroundJunctional adhesion molecule (JAM)‐A is an immunoglobulin‐like molecule that colocalizes with tight junctions (TJs) in endothelium and epithelium and is also found on blood leukocytes and platelets.ObjectiveWe aimed to elucidate the role of JAM‐A on airway hyperresponsiveness and inflammation in asthma using a murine asthma model, and to check blood level of JAM‐A in asthmatic patients.Methods;Using mice sensitized and challenged with OVA, as well as mice sensitized and challenged with saline, we investigated whether Jam‐a be involved in the pathogenesis of bronchial asthma. The level of JAM‐A was checked in the plasma of asthmatic patients and control subjects. The relation of JAM‐A with clinical variables in patients with asthma was searched.ResultsJAM‐A level had higher concentrations in plasma from patients with asthma (n = 19) than that of healthy controls (n = 12). JAM‐A level was correlated with FVC%, FEV1%, FEV1/FVC, total IgE, and blood lymphocyte proportion in patients with asthma. Jam‐a protein expression in lung tissue was significantly increased in OVA/OVA mice compared with control mice. Phospho‐JNK and phosphor‐ERK protein expression in lung tissue was significantly increased in OVA/OVA mice compared with control mice. A western blotting was used NHBE cells treated with HDM extracts for 4, 8 and 24 h. NHBE cells showed that HDM extracts resulted in increased JAM‐A, phospho‐JNK, phospho‐ERK expression.Conclusion;These data suggest that JAM‐A be elevated in plasma of patients with asthma, which raise the possibility that JAM‐A be involved in asthma through JNK and ERK pathway.

TIPE2 May Target the Nrf2/HO-1 Pathway to Inhibit M1 Macrophage-Related Neutrophilic Inflammation in Asthma.

PurposeAlthough recent studies have highlighted the link of TIPE2 and asthma airway inflammation, its roles and molecular mechanisms in different asthma inflammatory phenotypes remain largely unknown. We evaluated sputum TIPE2 expression level and its correlation with different asthma phenotypes. Additionally, we explored the roles and mechanism of TIPE2 in M1 polarization of macrophages.MethodsA total of 102 asthma patients who underwent sputum induction were enrolled to evaluate the expression level of TIPE2 and its association with different asthma phenotypes. To explore the roles and mechanism of TIPE2 in M1 polarization of macrophages, THP-1 monocytes stimulated with phorbol-12-myristate-13-acetate, were used as a model of undifferentiated (M0) macrophages, and M0 macrophages were treated with lipopolysaccharide to induce M1 macrophages.ResultsThe sputum TIPE2 level was significantly lower in patients with neutrophilic asthma (NA) and higher in patients with eosinophilic asthma (EA) compared with patients with paucigranulocytic asthma. The levels of IL-1β, TNF-α and IL-6 were highest in NA compared with other groups. TIPE2 levels in sputum negatively correlated with IL-1β and TNF-α levels but positively correlated with IL-4, IL-5, IL-13, and IL-10 levels (P < 0.05). In vitro, TIPE2 enhanced Nrf2/HO-1 pathway activation in macrophages and inhibited LPS-induced M1 macrophage differentiation and related cytokine release. Further analysis showed that the Nrf2 inhibitor ML385 weakened TIPE2-induced activation of the Nrf2/HO-1 pathway, as well as TIPE2-induced suppression in M1 polarization of macrophage and inflammatory cytokines secretion.ConclusionsTIPE2 expression level was highly down-regulated in NA and was negatively correlated with inflammatory factors (IL-1β and TNF-α). Aberrant expression of TIPE2 may target the Nrf2/HO-1 pathway to inhibit M1 macrophage–related neutrophilic inflammation in asthma.

T cell‐intrinsic miR‐155 is required for Th2 and Th17‐biased responses in acute and chronic airway inflammation by targeting several different transcription factors

Asthmatic airway inflammation is divided into two typical endotypes: Th2-mediated eosinophilic and Th1- or Th17-mediated neutrophilic airway inflammation. The miRNA miR-155 has well-documented roles in the regulation of adaptive T-cell responses and innate immunity. However, no specific cell-intrinsic role has yet been elucidated for miR-155 in T cells in the course of Th2-eosinophilic and Th17-neutrophilic airway inflammation using actual in vivo asthma models. Here, using conditional KO (miR155ΔCD4 cKO) mice that have the specific deficiency of miR-155 in T cells, we found that the specific deficiency of miR-155 in T cells resulted in fully suppressed Th2-type eosinophilic airway inflammation following acute allergen exposure, as well as greatly attenuated the Th17-type neutrophilic airway inflammation induced by repeated allergen exposure. Furthermore, miR-155 in T cells appeared to regulate the expression of several different target genes in the functional activation of CD4+ Th2 and Th17 cells. To be more precise, the deficiency of miR-155 in T cells enhanced the expression of c-Maf, SOCS1, Fosl2 and Jarid2 in the course of CD4+ Th2 cell activation, while C/EBPβ was highly enhanced in CD4+ Th17 cell activation in the absence of miR-155 expression. Conclusively, our data revealed that miR-155 could promote Th2 and Th17-mediated airway inflammation via the regulation of several different target genes, depending on the context of asthmatic diseases. Therefore, these results provide valuable insights into actual understanding of specific cell-intrinsic role of miR-155 in eosinophilic and neutrophilic airway inflammation for the development of fine-tune therapeutic strategies.

Sesamin Alleviates Asthma Airway Inflammation by Regulating Mitophagy and Mitochondrial Apoptosis.

Bronchial asthma poses a considerable burden on both individual patients and public health. Sesamin is a natural lignan that relieves asthma. However, the potential regulatory mechanism has not been fully validated. In this study, we revealed the mechanism of sesamin in inhibiting airway inflammation of asthma. In cockroach extract (CRE)-induced asthmatic mice, sesamin efficiently inhibited inflammatory cell infiltration, expressions of total and CRE-specific IgE in serum, and inflammatory cytokines (including IL-4, 5, 13) in bronchoalveolar lavage fluid. Further study revealed that sesamin inhibited Th2 cells in the mediastinal lymph nodes and spleen, the expression of PTEN-induced putative kinase 1 (PINK1) and Parkin, and apoptosis of lung airway epithelial cells. In vitro, sesamin had no significant cytotoxicity to BEAS-2B cells. Sesamin significantly increased TNF-α/IL-4-induced superoxide dismutase (SOD), catalase (CAT), heme oxygenase 1 (HO-1), and nuclear factor erythroid 2 related factor 2 (Nrf2), and decreased malondialdehyde. Sesamin also inhibited TNF-α/IL-4-induced mitochondrial reactive oxygen species, increased mitochondrial membrane potential, and reduced cell apoptosis as well as PINK1/Parkin expression and translocation to mitochondria. Conclusively, sesamin may relieve asthma airway inflammation by inhibiting mitophagy and mitochondrial apoptosis. Thus, sesamin may become a potential therapeutic agent for asthma.

Effect of daily tiotropium on allergen-induced early asthmatic responses and airway inflammation

Long-acting muscarinic antagonists (LAMAs) have been approved as an add-on treatment for moderate-to-severe asthma—tiotropium as an individual inhaler and umeclidinium as a combination inhaler. Data from ovalbumin-sensitized and challenged animals treated with muscarinic antagonists, including tiotropium, reveal reductions in inflammatory markers and allergen-associated changes.1,2 Inhaled muscarinic antagonists may, therefore, protect the airways of patients with allergic asthma through both bronchodilators (ie, decrease the early asthmatic response [EAR]) and anti-inflammatory action (ie, decrease type 2 [T2] eosinophilic airway inflammation).

Short isoform thymic stromal lymphopoietin reduces inflammation and aerobic glycolysis of asthmatic airway epithelium by antagonizing long isoform thymic stromal lymphopoietin

BackgroundUp-regulation of aerobic glycolysis has been reported as a characterization of asthma and facilitates airway inflammation. We has been previously reported that short isoform thymic stromal lymphopoietin (sTSLP) could reduce inflammation in asthmatic airway epithelial cells. Here we wanted to investigate whether the inhibition of sTSLP on asthma is related to aerobic glycolysis.MethodsAsthmatic model was established in challenging Male BALB/c mice and 16-HBE (human bronchial epithelial) cell line with house dust mite (HDM). Indicators of glycolysis were assessed to measure whether involve in sTSLP regulating airway epithelial cells inflammation in asthmatic model in vivo and in vitro.ResultssTSLP decreased inflammation of asthmatic airway and aerobic glycolysis in mice. HDM or long isoform thymic stromal lymphopoietin (lTSLP) promoted HIF-1α expression and aerobic glycolysis by miR-223 to target and inhibit VHL (von Hippel-Lindau) expression 16-HBE. Inhibition of aerobic glycolysis restrained HDM- and lTSLP-induced inflammatory cytokines production. sTSLP along had almost no potential to alter aerobic glycolysis of 16-HBE. But sTSLP decreased LDHA (lactate dehydrogenase A) and LD (Lactic acid) levels in BALF, and HIF-1α and LDHA protein levels in airway epithelial cells of asthma mice model. lTSLP and sTSLP both induced formation of TSLPR and IL-7R receptor complex, and lTSLP obviously facilitated phosphorylation of JAK1, JAK2 and STAT5, while sTSLP induced a little phosphorylation of JAK1 and STAT5.ConclusionWe identified a novel mechanism that lTSLP could promote inflammatory cytokines production by miR-223/VHL/HIF-1α pathway to upregulate aerobic glycolysis in airway epithelial cells in asthma. This pathway is suppressed by sTSLP through occupying binding site of lTSLP in TSLPR and IL-7R receptor complex.

Clostridium leptum induces the generation of interleukin-10+ regulatory B cells to alleviate airway inflammation in asthma

Background and objectiveAsthma is one of the most common chronic inflammatory diseases of the respiratory tract. Previous studies have shown that the reduction of regulatory B cells (Bregs) can increase inflammation of the body and promote the formation of chronic airway inflammation in asthma, but the detailed mechanisms have not been fully elucidated. The intestinal flora Clostridium leptum (CL) has been reported to modulate immune regulatory cells in the body, but the specific mechanisms are not clear. This study aimed to investigate the effects of CL on the differentiation of interleukin (IL)− 10+ Bregs and the regulation of the asthmatic inflammation-associated immune network. MethodsThe abundances of CL and the frequencies of blood Bregs from asthmatic patients and healthy controls were compared. The house dust mite (HDM)-induced asthma model was established in mice. The effects of CL exposure and B cell infusion on Breg differentiation, T cell cytokine production, and inflammatory cell infiltration in mouse lungs were examined. Bregs were cocultured with regulatory T cells (Tregs) and CD4+ non-Tregs to evaluate their roles on Foxp3 expression and T cell differentiation, respectively. ResultsCompared with healthy controls, asthmatic patients had significantly reduced frequencies of blood Bregs and abundances of fecal CL, and these two parameters were positively correlated. In the asthma model, the frequencies of Bregs in lungs were significantly reduced; while the infusion of Bregs isolated from CL- supplemented mice significantly reduced airway inflammation and hyperresponsiveness. In addition, Bregs inhibited the differentiation of cocultured non-Tregs into multiple effector cells and enhanced Foxp3 expression in cocultured Tregs. ConclusionBregs contribute to the alleviation of airway inflammation, which provides insight on implementing CL-based microbial induction of Bregs in asthma therapy.