Epithelial NF-κB Orchestrates House Dust Mite–Induced Airway Inflammation, Hyperresponsiveness, and Fibrotic Remodeling
Jane E. Tully,Sidra M. Hoffman,Karolyn G. Lahue,James D. Nolin,Vikas Anathy,Lennart K. A. Lundblad,Nirav Daphtary,Minara Aliyeva,Kendall E. Black,Anne E. Dixon,Matthew E. Poynter,Charles G. Irvin,Yvonne M. W. Janssen-Heininger +12 more
Reads0
Chats0
TLDR
It is demonstrated that following airway exposure with an asthma-relevant allergen, activation of classical and alternative NF-κB pathways occurs within the airway epithelium and may coordinately contribute to allergic inflammation, AHR, and fibrotic airway remodeling.Abstract:
NF-κB activation within the epithelium has been implicated in the pathogenesis of asthma, yet the exact role of epithelial NF-κB in allergen-induced inflammation and airway remodeling remains unclear. In the current study, we used an intranasal house dust mite (HDM) extract exposure regimen time course in BALB/c mice to evaluate inflammation, NF-κB activation, airway hyperresponsiveness (AHR), and airway remodeling. We used CC10-IκBαSR transgenic mice to evaluate the functional importance of epithelial NF-κB in response to HDM. After a single exposure of HDM, mRNA expression of proinflammatory mediators was significantly elevated in lung tissue of wild-type (WT) mice, in association with increases in nuclear RelA and RelB, components of the classical and alternative NF-κB pathway, respectively, in the bronchiolar epithelium. In contrast, CC10-IκBαSR mice displayed marked decreases in nuclear RelA and RelB and mRNA expression of proinflammatory mediators compared with WT mice. After 15 challenges with HDM, WT mice exhibited increases in inflammation, AHR, mucus metaplasia, and peribronchiolar fibrosis. CC10-IκBαSR transgenic mice displayed marked decreases in neutrophilic infiltration, tissue damping, and elastance parameters, in association will less peribronchiolar fibrosis and decreases in nuclear RelB in lung tissue. However, central airway resistance and mucus metaplasia remained elevated in CC10-IκBαSR transgenic mice, in association with the continued presence of lymphocytes, and partial decreases in eosinophils and IL-13. The current study demonstrates that following airway exposure with an asthma-relevant allergen, activation of classical and alternative NF-κB pathways occurs within the airway epithelium and may coordinately contribute to allergic inflammation, AHR, and fibrotic airway remodeling.read more
Citations
More filters
Journal ArticleDOI
Barrier Epithelial Cells and the Control of Type 2 Immunity
TL;DR: The general mechanisms of how different stimuli trigger type-2-cell-mediated immunity at mucosal barriers are reviewed and how this leads to protection or disease are reviewed.
Journal ArticleDOI
NF-kappaB Signaling in Chronic Inflammatory Airway Disease
TL;DR: Therapeutics which target NF-κB activation, including inhibitors of IκB kinases (IKKs) are potential treatments for asthma and COPD and reversing GR/histone acetylation shows promise as a strategy to treat steroid refractory airway disease by augmenting NF-σκB transrepression.
Journal ArticleDOI
Allergens and the airway epithelium response: Gateway to allergic sensitization
Bart N. Lambrecht,Hamida Hammad +1 more
TL;DR: Lung epithelial cells recognize allergens through expression of pattern recognition receptors and mount an innate immune response driven by activation of nuclear factor κB, which is crucial in determining the outcome of allergen inhalation.
Journal ArticleDOI
The role of macrolides in asthma: current evidence and future directions
TL;DR: The evidence from clinical trials is examined, macrolide properties and their relevance to the pathophysiology of asthma are discussed, and the use of macrolides in chronic asthma or acute exacerbations is not justified.
Journal ArticleDOI
Airway Epithelium Interactions with Aeroallergens: Role of Secreted Cytokines and Chemokines in Innate Immunity
TL;DR: The interactions of airway epithelial cells with allergens will be discussed with particular focus on interactions-mediated epithelial release of cytokines and chemokines and their role in the immune response.
References
More filters
Journal ArticleDOI
Signaling to NF-kappaB.
Matthew S. Hayden,Sankar Ghosh +1 more
TL;DR: An overview of established NF-kappaB signaling pathways is provided with focus on the current state of research into the mechanisms that regulate IKK activation and NF- kappaB transcriptional activity.
Journal ArticleDOI
Crosstalk in NF-κB signaling pathways
TL;DR: In this paper, a variety of stimuli coalesce on NF-κB activation, which can in turn mediate varied transcriptional programs, and the intricate crosstalk is crucial to shaping the diverse biological functions of NF-KB into cell type-and context-specific responses.
Journal ArticleDOI
Activation by IKKα of a Second, Evolutionary Conserved, NF-κB Signaling Pathway
Uwe Senftleben,Yixue Cao,Gutian Xiao,Florian R. Greten,Gertraud Krähn,Giuseppina Bonizzi,Yi Chen,Yinling Hu,Abraham Fong,Shao Cong Sun,Michael Karin +10 more
TL;DR: It is shown that IKKα is required for B cell maturation, formation of secondary lymphoid organs, increased expression of certain NF-κB target genes, and processing of the NF-σκB2 (p100) precursor.
Journal Article
Neutrophil Recruitment by Human IL-17 Via C-X-C Chemokine Release in the Airways
Martti Laan,Cui Zh,Hiroshi Hoshino,Jan Lötvall,Margareta Sjöstrand,Dieter C. Gruenert,Bengt-Eric Skoogh,Anders Lindén +7 more
TL;DR: It is demonstrated that hIL-17 can specifically and selectively recruit neutrophils into the airways via the release of C-X-C chemokines from bronchial epithelial cells and suggest a novel mechanism linking the activation of T-lymphocytes to recruitment of neutrophil into theAirways.
Journal ArticleDOI
IkappaB kinase complexes: gateways to NF-kappaB activation and transcription.
TL;DR: Nuclear IKK components have been found to act directly at the chromatin level of induced genes and to mediate responses to DNA damage, and IKK is engaged in cross talk with other pathways and confers functions independently of NF-κB.