scholarly journals Airway epithelial integrin β4 suppresses allergic inflammation by decreasing CCL17 production

2019 ◽  
Author(s):  
Lin Yuan ◽  
Xun Zhang ◽  
Ming Yang ◽  
Yizhou Zou ◽  
Yang Xiang ◽  
...  
Keyword(s):  
Allergic Asthma ◽  
Molecular Mechanisms ◽  
Allergic Inflammation ◽  
Airway Epithelial Cells ◽  
Th2 Cells ◽  
Airway Epithelial ◽  
Th2 Response ◽  
Integrin Β4 ◽  
Th2 Responses ◽  
Underlying Mechanisms

AbstractAirway epithelial cells (AECs) play a key role in asthma susceptibility and severity. Integrin β4 (ITGB4) is a structural adhesion molecule that is downregulated in the airway epithelium of asthma patients. Specific ITGB4 deficiency in AECs induces exaggerated Th2 responses, severe allergen-induced airway inflammation and airway hyperresponsiveness (AHR) in mouse model of allergic asthma. However, the underlying mechanisms remain unexplored. In this study, we determine the role of ITGB4 of AECs in the regulation of Th2 response and in the induction of asthma and identify the underpinning molecular mechanisms. We found that ITGB4 deficiency led to exaggerated Th2 cells infiltration, inflammation and AHR and higher production of CCL17 in HDM treated mice. ITGB4-regulated CCL17 production in AECs was regulated by EGFR, ERK and NF-κB pathways. EFGR-antagonist treatment or the neutralization of CCL17 by antibody inhibited exaggerated pathological marks in HDM-challenged ITGB4-deficient mice. Together, these results demonstrated that ITGB4 of AECs negatively regulates the development of Th2 responses of allergic asthma by down-regulation of EGFR and CCL17 pathway.

scholarly journals Airway epithelial integrin β4 suppresses allergic inflammation by decreasing CCL17 production

2020 ◽  
Vol 134 (13) ◽  
pp. 1735-1749 ◽  
Author(s):  
Lin Yuan ◽  
Xun Zhang ◽  
Ming Yang ◽  
Xizi Du ◽  
Leyuan Wang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Allergic Inflammation ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Th2 Response ◽  
Integrin Β4 ◽  
Dust Mite ◽  
Asthma Patients ◽  
Deficient Mice

Abstract Airway epithelial cells (AECs) play a key role in asthma susceptibility and severity. Integrin β4 (ITGB4) is a structural adhesion molecule that is down-regulated in the airway epithelium of asthma patients. Although a few studies hint toward the role of ITGB4 in asthmatic inflammation pathogenesis, their specific resultant effects remain unexplored. In the present study, we determined the role of ITGB4 of AECs in the regulation of Th2 response and identified the underpinning molecular mechanisms. We found that ITGB4 deficiency led to exaggerated lung inflammation and AHR with higher production of CCL17 in house dust mite (HDM)-treated mice. ITGB4 regulated CCL17 production in AECs through EGFR, ERK and NF-κB pathways. EFGR-antagonist treatment or the neutralization of CCL17 both inhibited exaggerated pathological marks in HDM-challenged ITGB4-deficient mice. Together, these results demonstrated the involvement of ITGB4 deficiency in the development of Th2 responses of allergic asthma by down-regulation of EGFR and CCL17 pathway in AECs.

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

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yuqing Mo ◽  
Ling Ye ◽  
Hui Cai ◽  
Guiping Zhu ◽  
Jian Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Allergic Asthma ◽  
Cd4 T Cells ◽  
Quantitative Polymerase Chain Reaction ◽  
Allergic Inflammation ◽  
Specific Ige ◽  
Th2 Cells ◽  
Th1 Cells ◽  
Th2 Response ◽  
Th1 And Th2

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

scholarly journals SERPINB10 Contributes to Asthma by Inhibiting the Apoptosis of Allergenic Th2 Cells

2020 ◽  
Author(s):  
Yuqing Mo ◽  
Ling Ye ◽  
Hui Cai ◽  
Guiping Zhu ◽  
Jian Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Allergic Asthma ◽  
Cd4 T Cells ◽  
Quantitative Polymerase Chain Reaction ◽  
Allergic Inflammation ◽  
Specific Ige ◽  
Th2 Cells ◽  
Th1 Cells ◽  
Th2 Response ◽  
Th1 And Th2

Abstract Background: Serine peptidase inhibitor, clade B, member 10 (SERPINB10) contributes to allergic inflammation in asthma. However, its role in the T-helper type 1 (Th1) /Th2 response of allergic asthma is not known. The goal of this study was to unveil the function of SERPINB10 in the Th2 response of allergic asthma and the mechanism by which SERPINB10 affects the viability of Th2 cells.Methods: Th2 cytokines and serum levels of house dust mite (HDM)-specific IgE in bronchoalveolar lavage fluid were examined by ELISA in an HDM-induced asthma model. The number and apoptosis of Th1 and Th2 cells in mouse lungs were measured by flow cytometry. Naïve CD4 T cells from patients with asthma were cultured under appropriate polarizing conditions to generate Th1 and Th2 cells. SERPINB10 expression in polarized Th1 and Th2 cells was quantified by real-time reverse transcription-quantitative polymerase chain reaction. SERPINB10 expression was knocked down in CD4 T cells with lentivirus. Results: Knockdown of SERPINB10 expression significantly diminished HDM-induced Th2 cytokine secretion and level of HDM-specific IgE. After HDM exposure, SERPINB10-knockdown mice had diminished numbers of Th2 cells, but similar numbers of Th1 cells, compared with those in negative-control mice. Th2 cells of SERPINB10-knockdown mice were more susceptible to apoptosis than that of control mice. Stimulating T-cell receptors (TCRs) with anti-CD3 antibody caused upregulation of SERPINB10 expression in polarized Th2 cells, but not polarized Th1 cells. Knockdown of SERPINB10 expression resulted in fewer numbers and greater apoptosis of polarized Th2 cells.Conclusion: Our results suggest that SERPINB10 may contributes to allergic inflammation and the Th2 response of asthma by inhibiting the apoptosis of Th2 cells.

scholarly journals Airway Epithelial Cells Are Crucial Targets of Glucocorticoids in a Mouse Model of Allergic Asthma

2017 ◽  
Vol 199 (1) ◽  
pp. 48-61 ◽  
Author(s):  
Carina Klaßen ◽  
Anna Karabinskaya ◽  
Lien Dejager ◽  
Sabine Vettorazzi ◽  
Justine Van Moorleghem ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Mouse Model ◽  
Allergic Asthma ◽  
Airway Epithelial Cells ◽  
Airway Epithelial

scholarly journals Responses of Airway Epithelium to Environmental Injury: Role in the Induction Phase of Childhood Asthma

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Rakesh K. Kumar ◽  
Jessica S. Siegle ◽  
Gerard E. Kaiko ◽  
Cristan Herbert ◽  
Joerg E. Mattes ◽  
...  
Keyword(s):  
Allergic Asthma ◽  
Childhood Asthma ◽  
Viral Infections ◽  
Environmental Pollutants ◽  
Immunological Response ◽  
Airway Epithelial Cells ◽  
Induction Phase ◽  
Airway Epithelial ◽  
Allergic Sensitisation

The pathogenesis of allergic asthma in childhood remains poorly understood. Environmental factors which appear to contribute to allergic sensitisation, with development of a Th2-biased immunological response in genetically predisposed individuals, include wheezing lower respiratory viral infections in early life and exposure to airborne environmental pollutants. These may activate pattern recognition receptors and/or cause oxidant injury to airway epithelial cells (AECs). In turn, this may promote Th2 polarisation via a “final common pathway” involving interaction between AEC, dendritic cells, and CD4+ T lymphocytes. Potentially important cytokines produced by AEC include thymic stromal lymphopoietin and interleukin-25. Their role is supported by in vitro studies using human AEC, as well as by experiments in animal models. To date, however, few investigations have employed models of the induction phase of childhood asthma. Further research may help to identify interventions that could reduce the risk of allergic asthma.

scholarly journals Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ivy Aneas ◽  
Donna C. Decker ◽  
Chanie L. Howard ◽  
Débora R. Sobreira ◽  
Noboru J. Sakabe ◽  
...  
Keyword(s):  
Association Studies ◽  
Regulatory Region ◽  
Airway Epithelial Cells ◽  
Genome Wide Association Studies ◽  
Airway Epithelial ◽  
Allele Specific ◽  
Enhancer Blocking ◽  
Underlying Mechanisms

AbstractGenome-wide association studies (GWAS) have implicated the IL33 locus in asthma, but the underlying mechanisms remain unclear. Here, we identify a 5 kb region within the GWAS-defined segment that acts as an enhancer-blocking element in vivo and in vitro. Chromatin conformation capture showed that this 5 kb region loops to the IL33 promoter, potentially regulating its expression. We show that the asthma-associated single nucleotide polymorphism (SNP) rs1888909, located within the 5 kb region, is associated with IL33 gene expression in human airway epithelial cells and IL-33 protein expression in human plasma, potentially through differential binding of OCT-1 (POU2F1) to the asthma-risk allele. Our data demonstrate that asthma-associated variants at the IL33 locus mediate allele-specific regulatory activity and IL33 expression, providing a mechanism through which a regulatory SNP contributes to genetic risk of asthma.

scholarly journals Protective effects of combined Mycobacterium bovis BCG and interleukin-12 vaccination on airway inflammation in a murine model of allergic asthma

2010 ◽  
Vol 33 (3) ◽  
pp. 196 ◽  
Author(s):  
Xia Ke ◽  
Jiangju Huang ◽  
Quan Chen ◽  
Suling Hong ◽  
Daoyin Zhu
Keyword(s):  
Airway Inflammation ◽  
Allergic Asthma ◽  
Mycobacterium Bovis ◽  
Immunoglobulin E ◽  
Allergic Airway Inflammation ◽  
Interleukin 12 ◽  
Protective Effects ◽  
Th2 Response ◽  
Bcg Vaccination ◽  
Th2 Responses

Purpose. Allergic asthma is characterized by chronic airway inflammation and airway hyperresponsiveness driven by allergen-specific T helper (Th)2 cells. Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccination has been documented to suppress Th2 responses and allergic airway inflammation in animal models. Since interleukin (IL)-12 is capable of inhibiting Th2 responses, we sought to investigate whether IL-12 could function as an adjuvant to increase the efficacy of BCG vaccination against allergic asthma. Methods. BALB/c neonatal mice (24 mice, 48-72 h old) were randomly divided into 3 subgroups (n = 8 for each group) to be immunized with PBS (control) or BCG with or without DNA plasmid-expressing IL-12. All of the mice were then sensitized and provoked with ovalbumin (OVA) to establish a model of allergic asthma. Results. Mice vaccinated with BCG alone showed a significant reduction in airway inflammation, percentage of eosinophils in bronchoalveolar lavage (BAL) fluid, and serum OVA-specific immunoglobulin E (IgE) levels in comparison with control animals. The suppressive effects of BCG were substantially augmented by the combination with IL-12. Furthermore, a decreased IL-4 and increased interferon-gamma (IFN-γ) production in BAL fluid were observed in animals inoculated with BCG alone or with IL-12 relative to control animals. Conclusion. Our data indicate that the combined vaccination with BCG and IL-12 yields a favorable outcome in prevention of experimental allergic airway inflammation, which is likely mediated through triggering a shift from a Th2 response to a Th1 response.

scholarly journals Inhaled house dust programs pulmonary dendritic cells to promote type 2 T-cell responses by an indirect mechanism

2015 ◽  
Vol 309 (10) ◽  
pp. L1208-L1218 ◽  
Author(s):  
Timothy P. Moran ◽  
Keiko Nakano ◽  
Gregory S. Whitehead ◽  
Seddon Y. Thomas ◽  
Donald N. Cook ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Allergic Asthma ◽  
House Dust ◽  
Lavage Fluid ◽  
Th2 Cells ◽  
T Helper 2 ◽  
Cell Responses ◽  
Th2 Responses ◽  
Th2 Differentiation

The induction of allergen-specific T helper 2 (Th2) cells by lung dendritic cells (DCs) is a critical step in allergic asthma development. Airway delivery of purified allergens or microbial products can promote Th2 priming by lung DCs, but how environmentally relevant quantities and combinations of these factors affect lung DC function is unclear. Here, we investigated the ability of house dust extract (HDE), which contains a mixture of environmental adjuvants, to prime Th2 responses against an innocuous inhaled antigen. Inhalational exposure to HDE conditioned lung conventional DCs, but not monocyte-derived DCs, to induce antigen-specific Th2 differentiation. Conditioning of DCs by HDE was independent of Toll-like receptor 4 signaling, indicating that environmental endotoxin is dispensable for programming DCs to induce Th2 responses. DCs directly treated with HDE underwent maturation but were poor stimulators of Th2 differentiation. In contrast, DCs treated with bronchoalveolar lavage fluid (BALF) from HDE-exposed mice induced robust Th2 differentiation. DC conditioning by BALF was independent of the proallergic cytokines IL-25, IL-33, and thymic stromal lymphopoietin. BALF treatment of DCs resulted in upregulation of CD80 but low expression of CD40, CD86, and IL-12p40, which was associated with Th2 induction. These findings support a model whereby environmental adjuvants in house dust indirectly program DCs to prime Th2 responses by triggering the release of endogenous soluble factor(s) by airway cells. Identifying these factors could lead to novel therapeutic targets for allergic asthma.

scholarly journals Looping of upstream cis-regulatory elements is required for CFTR expression in human airway epithelial cells

2020 ◽  
Vol 48 (7) ◽  
pp. 3513-3524 ◽  
Author(s):  
Monali NandyMazumdar ◽  
Shiyi Yin ◽  
Alekh Paranjapye ◽  
Jenny L Kerschner ◽  
Hannah Swahn ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Molecular Mechanisms ◽  
Gene Promoter ◽  
Regulatory Elements ◽  
Airway Epithelial Cells ◽  
Control Mechanisms ◽  
Airway Epithelial ◽  
Cell Type ◽  
Long Range Interactions ◽  
Cell Type Specific

Abstract The CFTR gene lies within an invariant topologically associated domain (TAD) demarcated by CTCF and cohesin, but shows cell-type specific control mechanisms utilizing different cis-regulatory elements (CRE) within the TAD. Within the respiratory epithelium, more than one cell type expresses CFTR and the molecular mechanisms controlling its transcription are likely divergent between them. Here, we determine how two extragenic CREs that are prominent in epithelial cells in the lung, regulate expression of the gene. We showed earlier that these CREs, located at −44 and −35 kb upstream of the promoter, have strong cell-type-selective enhancer function. They are also responsive to inflammatory mediators and to oxidative stress, consistent with a key role in CF lung disease. Here, we use CRISPR/Cas9 technology to remove these CREs from the endogenous locus in human bronchial epithelial cells. Loss of either site extinguished CFTR expression and abolished long-range interactions between these sites and the gene promoter, suggesting non-redundant enhancers. The deletions also greatly reduced promoter interactions with the 5′ TAD boundary. We show substantial recruitment of RNAPII to the −35 kb element and identify CEBPβ as a key activator of airway expression of CFTR, likely through occupancy at this CRE and the gene promoter.

scholarly journals Glucocorticoid and TNF signaling converge at A20 (TNFAIP3) to repress airway smooth muscle cytokine expression

2016 ◽  
Vol 311 (2) ◽  
pp. L421-L432 ◽  
Author(s):  
Sarah K. Sasse ◽  
Mohammed O. Altonsy ◽  
Vineela Kadiyala ◽  
Gaoyuan Cao ◽  
Reynold A. Panettieri ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Molecular Mechanisms ◽  
Nuclear Factor Κb ◽  
Airway Epithelial Cells ◽  
Therapeutic Effects ◽  
Target Tissue ◽  
Airway Epithelial ◽  
Fatal Asthma

Airway smooth muscle is a major target tissue for glucocorticoid (GC)-based asthma therapies, however, molecular mechanisms through which the GC receptor (GR) exerts therapeutic effects in this key airway cell type have not been fully elucidated. We previously identified the nuclear factor-κB (NF-κB) inhibitor, A20 (TNFAIP3), as a mediator of cytokine repression by glucocorticoids (GCs) in airway epithelial cells and defined cooperative regulation of anti-inflammatory genes by GR and NF-κB as a key mechanistic underpinning of airway epithelial GR function. Here, we expand on these findings to determine whether a similar mechanism is operational in human airway smooth muscle (HASM). Using HASM cells derived from normal and fatal asthma samples as an in vitro model, we demonstrate that GCs spare or augment TNF-mediated induction of A20 ( TNFAIP3), TNIP1, and NFKBIA, all implicated in negative feedback control of NF-κB-driven inflammatory processes. We applied chromatin immunoprecipitation and reporter analysis to show that GR and NF-κB directly regulate A20 expression in HASM through cooperative induction of an intronic enhancer. Using overexpression, we show for the first time that A20 and its interacting partner, TNIP1, repress TNF signaling in HASM cells. Moreover, we applied small interfering RNA-based gene knockdown to demonstrate that A20 is required for maximal cytokine repression by GCs in HASM. Taken together, our data suggest that inductive regulation of A20 by GR and NF-κB contributes to cytokine repression in HASM.

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