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Bronchial epithelial cell-derived extracellular vesicles drive inflammasome activation and NTHi infection in COPD

ABSTRACT: Extracellular vesicles (EVs) are lipid-membrane bound vesicles that can be beneficial or detrimental depending on the content they carry. As epithelial cells are the first line of defense against harmful particles, this work explored the role of COPD bronchial epithelial cell-derived EVs (CepEVs) in the pathogenesis and progression of chronic obstructive pulmonary disease (COPD). RNA sequencing of macrophages stimulated with CepEVs revealed the upregulation of various inflammasome-related genes, alongside significant IL-1b and IL-18 release, which could be attenuated with caspase-1 or NLRP3 inhibition. The proteome of CepEVs was also assessed, which highlighted a significant reduction in antibacterial proteins compared to healthy EVs (HepEVs). When functionally assessed in NTHi infection of THP-1 cells, pre-incubation with HepEVs stimulated NTHi clearance and reduced pro-inflammatory cytokine release by macrophages, which was reduced in CepEV-stimulated cells. This study shows for the first time that CepEVs are able to both prime and activate the inflammasome in healthy macrophages, and highlights EV-induced inflammasome inhibition as a potential therapeutic target for the dysregulated inflammation seen in COPD. Alongside the inflammasome, we were also able to show that CepEVs are deficient for multiple antibacterial proteins, and that one or more of these proteins are essential in mounting an immune response against NTHi in macrophages. This finding contributes to a potential therapeutic pipeline through the supplementation of the depleted antibacterial proteins in CepEVs, allowing for efficient bacterial clearance and reduced consequential inflammatory burden. CepEV co-incubation resulted in a persistent state of inflammation and infection. Both sets of findings contribute to the overall knowledge of COPD pathogenesis, and highlight epithelial EVs as key players in the propagation of inflammation and susceptibility to infection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313809 | GEO | 2025/12/22

REPOSITORIES: GEO

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Project description:Objectives: Therapies being safe, effective and not vulnerable to develop resistance are highly desirable to counteract bacterial infections. Host-directed therapeutics is an alternative to conventional antibiotics based on perturbing host pathways subverted by pathogens during their life cycle by the use of host-directed drugs to counteract microbial infections. This study sought to identify cellular genes and pathways differentially expressed during airways epithelial infection by nontypable Haemophilus influenzae (NTHi). NTHi is an opportunistic pathogen that is an important cause of exacerbation of chronic obstructive pulmonary disease (COPD). Based on the proposed relationship between NTHi intracellular location and persistence, the antimicrobial potential of a panel of drugs perturbing host pathways used by NTHi to enter epithelial cells was investigated. Methods: We screened for host genes differentially expressed upon infection by the clinical isolate NTHi375 by analyzing A549 cell whole genome expression profiling, and identified a panel of host target candidates which were pharmacologically modulated. Interfering drugs were tested for their bactericidal effect, cytotoxicity, effect on the interplay NTHi-epithelial cell, and effect on NTHi respiratory infection in vivo, by assessing lung bacterial loads in a murine intranasal infection model. Results: The sirtuin-1 activator resveratrol showed a bactericidal effect against NTHi; the PDE4 inhibitor rolipram showed therapeutic efficacy by lowering NTHi375 counts both intracellularly and in the lungs of infected mice. Conclusions: PDE4 inhibition is currently prescribed in COPD; resveratrol is a geroprotector attractive for COPD treatment by preventing lung aging. This work provides evidence for the antimicrobial potential of rolipram and resveratrol against NTHi respiratory infection. Haemophilus influenzae clinical strain NTHi375 induced gene expression in A549 human type II pneumocyte cell line was measured at 2 h post-infection. Non infected cells were used as a control. Four independent experiments were performed for each condition.

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Bronchial epithelial cell-derived extracellular vesicles drive inflammasome activation and NTHi infection in COPD

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