Airway epithelial integrin β4 suppresses allergic inflammation by decreasing CCL17 production

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.

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Airway epithelial integrin β4 suppresses allergic inflammation by decreasing CCL17 production

10.1101/513499 ◽

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.

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Cross-reactive antibodies against dust mite-derived enolase induce neutrophilic airway inflammation

European Respiratory Journal ◽

10.1183/13993003.02375-2019 ◽

2020 ◽

pp. 1902375 ◽

Cited By ~ 1

Author(s):

Jianli Lin ◽

Nana Huang ◽

Jing Li ◽

Xiaoyu Liu ◽

Qing Xiong ◽

...

Keyword(s):

Airway Inflammation ◽

Common Factor ◽

Airway Epithelial Cells ◽

Epithelial Barrier ◽

Airway Epithelial ◽

Epithelial Barrier Function ◽

Neutrophilic Inflammation ◽

Dust Mite ◽

Asthma Patients

Background and aimsNeutrophilic inflammation is a hallmark of some specific asthma phenotypes; its etiology is not fully understood yet. House dust mite (HDM) is the most common factor involving with the pathogenesis of airway inflammation. This study aims to elucidate the role of cross-antibodies against HDM-derived factors in the development of neutrophilic inflammation in the airway.MethodsBlood samples were collected from asthma patients with chronic neutrophilic asthma to be analysed the HDM-specific cross-reactive antibodies. The role of an antibody against HDM-derived enolase (EnoAb) in the impairment of airway epithelial barrier function and induction of airway inflammation was assessed in a cell culture model and an animal model.ResultsHigh similarity (72%) of the enolase gene sequences was identified between HDM and human. Serum EnoAb was detected in patients with chronic neutrophilic asthma. The EnoAb bound to airway epithelial cells to form complexes with enolase, which activated complements, impaired airway epithelial barrier functions and induced neutrophilic inflammation in the airway tissues.ConclusionsHDM-derived enolase can induce specific cross-antibodies by human, which induce neutrophilic inflammation in the airway.

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Significance of Interleukin (IL)-4 and IL-13 in Inflammatory Arthritis

Cells ◽

10.3390/cells10113000 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3000

Author(s):

Milena Iwaszko ◽

Sylwia Biały ◽

Katarzyna Bogunia-Kubik

Keyword(s):

Inflammatory Arthritis ◽

Current Knowledge ◽

Allergic Inflammation ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

T Helper ◽

T Helper 2 ◽

Th2 Cytokine ◽

Inflammatory Processes

Interleukin (IL)-4 and IL-13 belong to the T helper 2 (Th2) cytokine family, along with IL-3, IL-5, and IL-9. These cytokines are key mediators of allergic inflammation. They have important immunomodulatory activities and exert influence on a wide variety of immune cells, such as B cells, eosinophils, basophils, monocytes, fibroblasts, endothelial cells, airway epithelial cells, smooth muscle cells, and keratinocytes. Recent studies have implicated IL-4 and IL-13 in the development of various autoimmune diseases. Additionally, these cytokines have emerged as potential players in pathogenesis of inflammatory arthritis. Recent findings suggest that the IL-4 and IL-13 might play a significant role in the downregulation of inflammatory processes underlying RA pathology, and beneficially modulate the course of the disease. This review summarizes the biological features of the IL-4 and IL-13 and provides current knowledge regarding the role of these cytokines in inflammatory arthritis.

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Airway epithelial cell necroptosis contributes to asthma exacerbation in a mouse model of house dust mite-induced allergic inflammation

Mucosal Immunology ◽

10.1038/s41385-021-00415-5 ◽

2021 ◽

Author(s):

Nikos Oikonomou ◽

Martjin J. Schuijs ◽

Antonis Chatzigiagkos ◽

Ariadne Androulidaki ◽

Vassilis Aidinis ◽

...

Keyword(s):

Cell Death ◽

Epithelial Cell ◽

Mouse Model ◽

House Dust ◽

House Dust Mite ◽

Airway Epithelial Cell ◽

Allergic Inflammation ◽

Airway Epithelial ◽

Dust Mite

AbstractRegulation of epithelial cell death has emerged as a key mechanism controlling immune homeostasis in barrier surfaces. Necroptosis is a type of regulated necrotic cell death induced by receptor interacting protein kinase 3 (RIPK3) that has been shown to cause inflammatory pathologies in different tissues. The role of regulated cell death and particularly necroptosis in lung homeostasis and disease remains poorly understood. Here we show that mice with Airway Epithelial Cell (AEC)-specific deficiency of Fas-associated with death domain (FADD), an adapter essential for caspase-8 activation, developed exacerbated allergic airway inflammation in a mouse model of asthma induced by sensitization and challenge with house dust mite (HDM) extracts. Genetic inhibition of RIPK1 kinase activity by crossing to mice expressing kinase inactive RIPK1 as well as RIPK3 or MLKL deficiency prevented the development of exaggerated HDM-induced asthma pathology in FADDAEC-KO mice, suggesting that necroptosis of FADD-deficient AECs augmented the allergic immune response. These results reveal a role of AEC necroptosis in amplifying airway allergic inflammation and suggest that necroptosis could contribute to asthma exacerbations caused by respiratory virus infections inducing AEC death.

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PI3Kγ-deficient mice have reduced levels of allergen-induced eosinophilic inflammation and airway remodeling

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.90275.2008 ◽

2009 ◽

Vol 296 (2) ◽

pp. L210-L219 ◽

Cited By ~ 39

Author(s):

Dae Hyun Lim ◽

Jae Youn Cho ◽

Dae Jin Song ◽

Sang Yeub Lee ◽

Marina Miller ◽

...

Keyword(s):

Airway Remodeling ◽

Allergen Challenge ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Eosinophilic Inflammation ◽

Significant Difference ◽

Phosphoinositide 3 Kinase ◽

Blood Eosinophils ◽

Deficient Mice

In this study, we have examined the role of phosphoinositide 3 kinase γ (PI3Kγ), a class Ib PI3K, in contributing to airway remodeling utilizing PI3Kγ-deficient mice exposed to chronic allergen challenge. Wild-type (WT) mice sensitized to ovalbumin (OVA) and chronically challenged with OVA for 1 mo developed significantly increased levels of eosinophilic inflammation and airway remodeling. In contrast, PI3Kγ-deficient mice challenged with OVA had significantly reduced numbers of bronchoalveolar lavage and peribronchial eosinophils compared with WT mice. There was no significant difference in the number of bone marrow or circulating peripheral blood eosinophils when comparing WT mice and PI3Kγ-deficient mice, suggesting that trafficking of eosinophils into the lung was reduced in PI3Kγ-deficient mice. PI3Kγ-deficient and WT mice had similar levels of IL-5 and eotaxin-1. The reduced eosinophil recruitment to the airway in PI3Kγ-deficient mice challenged with OVA was associated with significantly reduced numbers of TGF-β1+ peribronchial cells, reduced numbers of pSmad 2/3+ airway epithelial cells, and pSmad 2/3+ peribronchial cells, as well as significantly reduced levels of peribronchial fibrosis (quantitated by trichrome staining and image analysis as well as by lung collagen levels). In addition, the area of peribronchial α-smooth muscle staining was significantly reduced in PI3Kγ-deficient compared with WT mice. Overall, this study demonstrates an important role for PI3Kγ in mediating allergen-induced eosinophilic airway inflammation and airway remodeling, suggesting that PI3Kγ may be a novel therapeutic target in asthma.

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CDH26 amplifies airway epithelial IL-4 receptor α signaling in asthma

10.1101/2020.12.01.20241752 ◽

2020 ◽

Author(s):

Yuchen Feng ◽

Shengchong Chen ◽

Chenli Chang ◽

Wenliang Wu ◽

Dian Chen ◽

...

Keyword(s):

Epithelial Cells ◽

Airway Epithelial Cells ◽

Bronchial Epithelial Cells ◽

Allergic Airway Disease ◽

Airway Epithelial ◽

Mucus Production ◽

Bronchial Epithelial ◽

Asthma Patients ◽

Airway Mucus

ABSTRACTBackgroundActivation of interleukin (IL)-4 receptor (R) signaling in airway epithelial cells leads to airway hyperresponsiveness and mucus overproduction in asthma. Cadherin-26 (CDH26), a cadherin implicated in polarization of airway epithelial cells, is upregulated in asthma. However, the role of CDH26 in asthma remains unknown. We hypothesize that CDH26 plays a role in airway epithelial IL-4R signaling in asthma.MethodsWe measured airway resistance, mucus production, airway inflammation, and Il-4Rα expression in Cdh26-/- and WT mice after allergen sensitization and challenge. We explored the role of CDH26 in IL-4R signaling, mucin genes and eosinophilic chemokine expression in cultured bronchial epithelial cells and bronchial brushings from asthma patients.ResultsCdh26 deficiency nearly blocked airway mucus overproduction, and suppressed AHR and airway eosinophilia in a murine model of allergic airway disease. Interestingly, Il-4Rα expression in airway epithelium was markedly reduced in Cdh26-/- mice. In cultured human bronchial epithelial cells, CDH26 knockdown inhibited IL-13, a ligand for IL-4R, -induced IL-4Rα and IL-13Rα1 expression, and suppressed the downstream Jak1 and Stat6 phosphorylation. Moreover, CDH26 knockdown inhibited IL-13-induced MUC5AC, MUC5B and eosinophilic chemokines CCL11, CCL24, CCL26 expression. In contrast, CDH26 overexpression intensified IL-13-induced activation of IL-4Rα signaling. In asthma patients, CDH26 was the only one upregulated of 11 cadherins in bronchial brushings. CDH26 expression significantly correlated with epithelial IL-4Rα, MUC5AC expression, sputum eosinophilia and fractional exhaled nitric oxide (FeNO).ConclusionTaken together, CDH26 is an amplifier of epithelial IL-4R signaling in asthma, and may represent a therapeutic target for airway mucus overproduction.

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Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional

Nature Communications ◽

10.1038/s41467-021-24853-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ian T. Stancil ◽

Jacob E. Michalski ◽

Duncan Davis-Hall ◽

Hong Wei Chu ◽

Jin-Ah Park ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Airway Epithelium ◽

Cell Types ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Airway Epithelia ◽

Chronic Lung Diseases ◽

Distal Airway ◽

Signaling Axis

AbstractThe airway epithelium serves as the interface between the host and external environment. In many chronic lung diseases, the airway is the site of substantial remodeling after injury. While, idiopathic pulmonary fibrosis (IPF) has traditionally been considered a disease of the alveolus and lung matrix, the dominant environmental (cigarette smoking) and genetic (gain of function MUC5B promoter variant) risk factor primarily affect the distal airway epithelium. Moreover, airway-specific pathogenic features of IPF include bronchiolization of the distal airspace with abnormal airway cell-types and honeycomb cystic terminal airway-like structures with concurrent loss of terminal bronchioles in regions of minimal fibrosis. However, the pathogenic role of the airway epithelium in IPF is unknown. Combining biophysical, genetic, and signaling analyses of primary airway epithelial cells, we demonstrate that healthy and IPF airway epithelia are biophysically distinct, identifying pathologic activation of the ERBB-YAP axis as a specific and modifiable driver of prolongation of the unjammed-to-jammed transition in IPF epithelia. Furthermore, we demonstrate that this biophysical state and signaling axis correlates with epithelial-driven activation of the underlying mesenchyme. Our data illustrate the active mechanisms regulating airway epithelial-driven fibrosis and identify targets to modulate disease progression.

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