Innate Lymphoid Cells Are Required to Induce Airway Hyperreactivity in a Murine Neutrophilic Asthma Model

Jonckheere, Anne‐Charlotte; Seys, Sven; Steelant, Brecht; Decaesteker, Tatjana; Dekoster, Kaat; Cremer, Jonathan; Dilissen, Ellen; Schols, Dominique; Iwakura, Yoichiro; Velde, Greetje Vande; Breynaert, Christine; Schrijvers, R.; Vanoirbeek, Jeroen; Ceuppens, Jan; Dupont, Lieven; Bullens, Dominique

doi:10.3389/fimmu.2022.849155

Cited by 8 publications

(6 citation statements)

References 64 publications

(95 reference statements)

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“…37 In a similar model, repeated low dose nasal endotoxin challenge enhanced AHR, BAL neutrophilia and elevated levels of IL‐17A and IL‐22. 38 Furthermore, the combination of IL‐22 with IL‐17, but neither alone, elicited AHR in naïve mice and both elicited proinflammatory mediator release from primary HBECs. RORγt blockade in a Th2 low mouse model of asthma suppressed both IL‐17 and IL‐22 expression and attenuated AHR and neutrophilia.…”

Section: Discussionmentioning

confidence: 99%

Endotypes of severe neutrophilic and eosinophilic asthma from multi‐omics integration of U‐BIOPRED sputum samples

Kermani,

Li,

Versi

et al. 2024

Clinical & Translational Med

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BackgroundClustering approaches using single omics platforms are increasingly used to characterise molecular phenotypes of eosinophilic and neutrophilic asthma. Effective integration of multi‐omics platforms should lead towards greater refinement of asthma endotypes across molecular dimensions and indicate key targets for intervention or biomarker development.ObjectivesTo determine whether multi‐omics integration of sputum leads to improved granularity of the molecular classification of severe asthma.MethodsWe analyzed six ‐omics data blocks–microarray transcriptomics, gene set variation analysis of microarray transcriptomics, SomaSCAN proteomics assay, shotgun proteomics, 16S microbiome sequencing, and shotgun metagenomic sequencing–from induced sputum samples of 57 severe asthma patients, 15 mild‐moderate asthma patients, and 13 healthy volunteers in the U‐BIOPRED European cohort. We used Monti consensus clustering algorithm for aggregation of clustering results and Similarity Network Fusion to integrate the 6 multi‐omics datasets of the 72 asthmatics.ResultsFive stable omics‐associated clusters were identified (OACs). OAC1 had the best lung function with the least number of severe asthmatics with sputum paucigranulocytic inflammation. OAC5 also had fewer severe asthma patients but the highest incidence of atopy and allergic rhinitis, with paucigranulocytic inflammation. OAC3 comprised only severe asthmatics with the highest sputum eosinophilia. OAC2 had the highest sputum neutrophilia followed by OAC4 with both clusters consisting of mostly severe asthma but with more ex/current smokers in OAC4. Compared to OAC4, there was higher incidence of nasal polyps, allergic rhinitis, and eczema in OAC2. OAC2 had microbial dysbiosis with abundant Moraxella catarrhalis and Haemophilus influenzae. OAC4 was associated with pathways linked to IL‐22 cytokine activation, with the prediction of therapeutic response to anti‐IL22 antibody therapy.ConclusionMulti‐omics analysis of sputum in asthma has defined with greater granularity the asthma endotypes linked to neutrophilic and eosinophilic inflammation. Modelling diverse types of high‐dimensional interactions will contribute to a more comprehensive understanding of complex endotypes.Key Points Unsupervised clustering on sputum multi‐omics of asthma subjects identified 3 out of 5 clusters with predominantly severe asthma. One severe asthma cluster was linked to type 2 inflammation and sputum eosinophilia while the other 2 clusters to sputum neutrophilia. One severe neutrophilic asthma cluster was linked to Moraxella catarrhalis and to a lesser extent Haemophilus influenzae while the second cluster to activation of IL‐22.

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Section: Discussionmentioning

confidence: 99%

Endotypes of severe neutrophilic and eosinophilic asthma from multi‐omics integration of U‐BIOPRED sputum samples

Kermani,

Li,

Versi

et al. 2024

Clinical & Translational Med

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“…BAL fluid was centrifuged for 10 min at 1000× g at 4 • C. The supernatant was collected and stored at −80 • C until further use, and the pellet was resuspended in 1 mL 0.9% NaCl solution. Total viable cell count was determined using a Trypan blue staining (BioWhittaker ® Lonza, Basel, Switzerland) and counted on a Bürker haemocytometer [47]. Cells were prepared for differential cell count by spinning 250 µL of cells (Cytospin 3, Shandon, TechGen, Zellik, Belgium) at 1400× g for six minutes on microscope slides.…”

Section: Differential Cell Countsmentioning

confidence: 99%

A Multimodal Imaging-Supported Down Syndrome Mouse Model of RSV Infection

Tielemans

Herdt

Pollenus

et al. 2023

Viruses

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Individuals with Down syndrome (DS) are more prone to develop severe respiratory tract infections. Although a RSV infection has a high clinical impact and severe outcome in individuals with DS, no vaccine nor effective therapeutics are available. Any research into infection pathophysiology or prophylactic and therapeutic antiviral strategies in the specific context of DS would greatly benefit this patient population, but currently such relevant animal models are lacking. This study aimed to develop and characterize the first mouse model of RSV infection in a DS-specific context. Ts65Dn mice and wild type littermates were inoculated with a bioluminescence imaging-enabled recombinant human RSV to longitudinally track viral replication in host cells throughout infection progression. This resulted in an active infection in the upper airways and lungs with similar viral load in Ts65Dn mice and euploid mice. Flow cytometric analysis of leukocytes in lungs and spleen demonstrated immune alterations with lower CD8+ T cells and B-cells in Ts65Dn mice. Overall, our study presents a novel DS-specific mouse model of hRSV infection and shows that potential in using the Ts65Dn preclinical model to study immune-specific responses of RSV in the context of DS and supports the need for models representing the pathological development.

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“…These techniques can be applied to multiple models of lung disease development and progression, such as tumor studies, lung transplantation, lung development models, exposure-induced models and in longitudinal studies involving therapeutic intervention. Several novel techniques for image acquisition and analysis have been recently published [1,2,[17][18][19], however, a standardized method has yet to be established, and there are currently limited published resources for investigators to determine appropriate imaging and analysis approaches to meet study requirements. Herein, we describe four approaches to microCT with detailed methodological information and discussion of advantages and limitations of each approach.…”

Section: Introductionmentioning

confidence: 99%

Application-specific approaches to MicroCT for evaluation of mouse models of pulmonary disease

et al. 2023

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The advent of micro-computed tomography (microCT) has provided significant advancement in our ability to generate clinically relevant assessments of lung health and disease in small animal models. As microCT use to generate outcomes analysis in pulmonary preclinical models has increased there have been substantial improvements in image quality and resolution, and data analysis software. However, there are limited published methods for standardized imaging and automated analysis available for investigators. Manual quantitative analysis of microCT images is complicated by the presence of inflammation and parenchymal disease. To improve the efficiency and limit user-associated bias, we have developed an automated pulmonary air and tissue segmentation (PATS) task list to segment lung air volume and lung tissue volume for quantitative analysis. We demonstrate the effective use of the PATS task list using four distinct methods for imaging, 1) in vivo respiration controlled scanning using a flexiVent, 2) longitudinal breath-gated in vivo scanning in resolving and non-resolving pulmonary disease initiated by lipopolysaccharide-, bleomycin-, and silica-exposure, 3) post-mortem imaging, and 4) ex vivo high-resolution scanning. The accuracy of the PATS task list was compared to manual segmentation. The use of these imaging techniques and automated quantification methodology across multiple models of lung injury and fibrosis demonstrates the broad applicability and adaptability of microCT to various lung diseases and small animal models and presents a significant advance in efficiency and standardization of preclinical microCT imaging and analysis for the field of pulmonary research.

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Innate Lymphoid Cells Are Required to Induce Airway Hyperreactivity in a Murine Neutrophilic Asthma Model

Cited by 8 publications

References 64 publications

Endotypes of severe neutrophilic and eosinophilic asthma from multi‐omics integration of U‐BIOPRED sputum samples

Endotypes of severe neutrophilic and eosinophilic asthma from multi‐omics integration of U‐BIOPRED sputum samples

A Multimodal Imaging-Supported Down Syndrome Mouse Model of RSV Infection

Application-specific approaches to MicroCT for evaluation of mouse models of pulmonary disease

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