Biology subjects

Magnen, M.

Publications and source records attributed to Magnen, M..

6 recordsLinked to original sources

bioRxiv2025

Fibroblast orchestration of inflammaging via NF-kB activation

Aged tissue is characterized by chronic inflammation known as "inflammaging". While this aging immune phenotype supposedly drives some of the most common diseases affecting the elderly, little is known about the structural drivers of inflammaging. In this study, we demonstrate that age-dependent activation of NF-kB in tissue fibroblasts remodels the immune architecture, promoting the emergence of an exhausted T cell population (GZMK+/CD8+) recently identified in normal aging, as well as autoimmunity and cancer. Fibroblast-specific NF-kB activation triggered a fibroblast-macrophage-T cell circuit to form tertiary lymphoid structures in the lung and promoted the emergence of exhausted GZMK+ T cells. Fibroblastic activation of NF-kB increased host susceptibility to acute lung injury and mimics severe pneumonia commonly seen in elderly patients, which was alleviated by deletion of GZMK+ T cells. Our data provide a structural basis for inflammaging, where fibroblasts orchestrate the complex immune aging phenotype in non-immune tissues, increasing susceptibility to age-related diseases. Highlights- Bronchus-associated lymphoid tissue (BALT) enriched for GZMK+ T cells develop with age - Lung adventitial fibroblasts demonstrate increased NF-kB activation with age. - Fibroblast activation of NF-kB in young animals recapitulates multiple features of normal lung immune aging - Depletion of GZMK+ cells decreases lung inflammation in a mouse model of acute respiratory distress syndrome (ARDS)

immunology↗

bioRxiv2025

Furin Inhibition Protects Against Acute Lung Injury in a Mouse Model of Pseudomonas Aeruginosa Infection

Pseudomonas aeruginosa (PA) is responsible for significant morbidity and mortality particularly in patients with chronic lung diseases such as chronic obstructive pulmonary disease (COPD), bronchiectasis, cystic fibrosis (CF) as well as hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). The rise of antibiotic-resistant PA strains necessitates alternative treatment strategies. Among the different toxins secreted by PA, Exotoxin-A (Exo-A) becomes cytotoxic when cleaved by furin. This study investigates the therapeutic potential of furin inhibitor BOS-318 in mitigating acute lung injury induced by Exo-A and PA infection. Furin inhibition significantly improved survival rates and reduced lung injury in mouse pneumonia models using Exo-A and PA103. Additionally, BOS-318 accelerated bacterial clearance in vivo, and increased phagocytosis by alveolar macrophages. Bulk RNA-seq immune profiling revealed modulation of the natural killer (NK) cell signaling pathway possibly due to a decrease in NK recruitment, suggesting a role of furin in shaping the immune response. Overall, our findings demonstrate that furin inhibition protects against PA-induced acute lung injury and hastens bacterial clearance. These results are the first to characterize furin inhibition in animal models and supports its potential use as an adjunctive therapeutic strategy for treating PA infections.

immunology↗

bioRxiv2024

Loss of neutrophil Shp1 produces hemorrhagic and lethal acute lung injury

The acute respiratory distress syndrome (ARDS) is associated with significant morbidity and mortality and neutrophils are critical to its pathogenesis. Neutrophil activation is closely regulated by inhibitory tyrosine phosphatases including Src homology region 2 domain containing phosphatase-1 (Shp1). Here, we report that loss of neutrophil Shp1 in mice produced hyperinflammation and lethal pulmonary hemorrhage in sterile inflammation and pathogen-induced models of acute lung injury (ALI) through a Syk kinase-dependent mechanism. We observed large intravascular neutrophil clusters, perivascular inflammation, and excessive neutrophil extracellular traps in neutrophil-specific Shp1 knockout mice suggesting an underlying mechanism for the observed pulmonary hemorrhage. Targeted immunomodulation through the administration of a Shp1 activator (SC43) reduced agonist-induced reactive oxygen species in vitro and ameliorated ALI-induced alveolar neutrophilia and NETs in vivo. We propose that the pharmacologic activation of Shp1 has the potential to fine-tune neutrophil hyperinflammation that is central to the pathogenesis of ARDS.

immunology↗

bioRxiv2023

Optimizing anesthesia and delivery approaches for dosing into lungs of mice

Microbes, toxins, therapeutics and cells are often instilled into lungs of mice to model diseases and test experimental interventions. Consistent pulmonary delivery is critical for experimental power and reproducibility, but we observed variation in outcomes between handlers using different anesthetic approaches for intranasal dosing into mice. We therefore used a radiotracer to quantify lung delivery after intranasal dosing under inhalational (isoflurane) versus injectable (ketamine/xylazine) anesthesia in C57BL/6 mice. We found that ketamine/xylazine anesthesia resulted in delivery of a greater proportion (52{+/-}9%) of an intranasal dose to lungs relative to isoflurane anesthesia (30{+/-}15%). This difference in pulmonary dose delivery altered key outcomes in models of viral and bacterial pneumonia, with mice anesthetized with ketamine/xylazine for intranasal infection with influenza A virus or Pseudomonas aeruginosa developing more robust lung inflammation responses relative to control animals randomized to isoflurane anesthesia. Pulmonary dosing efficiency through oropharyngeal aspiration was not affected by anesthetic method and resulted in delivery of 63{+/-}8% of dose to lungs, and a non-surgical intratracheal dosing approach further increased lung delivery to 92{+/-}6% of dose. Use of either of these more precise dosing methods yielded greater experimental power in the bacterial pneumonia model relative to intranasal infection. Both anesthetic approach and dosing route can impact pulmonary dosing efficiency. These factors affect experimental power and so should be considered when planning and reporting studies involving delivery of fluids to lungs of mice. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=158 SRC="FIGDIR/small/526706v2_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@10e90forg.highwire.dtl.DTLVardef@34f8a5org.highwire.dtl.DTLVardef@1b02406org.highwire.dtl.DTLVardef@10d3f33_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2022

Immediate myeloid depot for SARS-CoV-2 in the human lung

In the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, considerable focus has been placed on a model of viral entry into host epithelial populations, with a separate focus upon the responding immune system dysfunction that exacerbates or causes disease. We developed a precision-cut lung slice model to investigate very early host-viral pathogenesis and found that SARS-CoV-2 had a rapid and specific tropism for myeloid populations in the human lung. Infection of alveolar macrophages was partially dependent upon their expression of ACE2, and the infections were productive for amplifying virus, both findings which were in contrast with their neutralization of another pandemic virus, Influenza A virus (IAV). Compared to IAV, SARS-CoV-2 was extremely poor at inducing interferon-stimulated genes in infected myeloid cells, providing a window of opportunity for modest titers to amplify within these cells. Endotracheal aspirate samples from humans with the acute respiratory distress syndrome (ARDS) from COVID-19 confirmed the lung slice findings, revealing a persistent myeloid depot. In the early phase of SARS-CoV-2 infection, myeloid cells may provide a safe harbor for the virus with minimal immune stimulatory cues being generated, resulting in effective viral colonization and quenching of the immune system.

immunology↗

bioRxiv2020

Global Absence and Targeting of Protective Immune States in Severe COVID-19.

While SARS-CoV-2 infection has pleiotropic and systemic effects in some patients, many others experience milder symptoms. We sought a holistic understanding of the severe/mild distinction in COVID-19 pathology, and its origins. We performed a whole-blood preserving single-cell analysis protocol to integrate contributions from all major cell types including neutrophils, monocytes, platelets, lymphocytes and the contents of serum. Patients with mild COVID-19 disease display a coordinated pattern of interferon-stimulated gene (ISG) expression across every cell population and these cells are systemically absent in patients with severe disease. Severe COVID-19 patients also paradoxically produce very high anti-SARS-CoV-2 antibody titers and have lower viral load as compared to mild disease. Examination of the serum from severe patients demonstrates that they uniquely produce antibodies with multiple patterns of specificity against interferon-stimulated cells and that those antibodies functionally block the production of the mild disease-associated ISG-expressing cells. Overzealous and auto-directed antibody responses pit the immune system against itself in many COVID-19 patients and this defines targets for immunotherapies to allow immune systems to provide viral defense. One Sentence SummaryIn severe COVID-19 patients, the immune system fails to generate cells that define mild disease; antibodies in their serum actively prevents the successful production of those cells.

immunology↗