Biology subjects

Meilhac, O.

Publications and source records attributed to Meilhac, O..

3 recordsLinked to original sources

bioRxiv2025

Aerosolized ApoA1 Nanoparticles Synthesized by Microfluidics Cross the Lung Barrier and Modulate Inflammation

High-density lipoproteins exert vasculoprotective effects, mainly through apolipoprotein A1, which has led to the development of treatments based on apolipoprotein A1 nanoparticles (A1NPs) administered intravenously, mainly for the treatment of cardiovascular diseases. However, their potential as therapy for lung pathologies has not yet been explored. In this work, we produced A1NPs using microfluidics and characterized their therapeutic potential for lung delivery. Their morphology was characterized by dynamic light scattering and transmission electron microscopy. A1NPs toxicity and cellular uptake were performed on both endothelial (HMEC-1) and epithelial (A549) cells and their anti-inflammatory activity was evaluated on TNF--stimulated HMEC-1. A1NPs biodistribution was explored in lung mice after aerosolization and their transcytosis was further investigated using A549 air-liquid interface model. Our results demonstrate that the microfluidic synthesis of A1NPs was reproducible and yielded discoidal particles with sizes ranging from 7-12 nm. A1NPs were internalized by both cells without being cytotoxic and significantly reduced IL-6 expression. Aerosolization resulted in homogeneous distribution in lungs, without causing an immunogenic response. A fraction of A1NPs crossed alveolar epithelial cells both in vitro and in vivo, paving the way for future therapeutic strategies targeting not only the lungs, but also other peripheral organs. These results are promising for the use of A1NPs as vectors for therapeutic molecules, which could exert synergistic protective effects with Apolipoprotein A1. This is the first study to show the non-invasive administration of A1NPs by aerosolization, which may improve their bioavailability in lungs and appears to be a promising approach for treating lung diseases. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/663869v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@2f3436org.highwire.dtl.DTLVardef@10cd3aeorg.highwire.dtl.DTLVardef@11d7542org.highwire.dtl.DTLVardef@fd627a_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2024

PCSK9 deficiency promotes the development of peripheral neuropathy

PCSK9 best-known and studied function is to induce the hepatic degradation of the low-density lipoprotein receptor (LDLR), thereby increasing the concentration of LDL-cholesterol (LDL-C) in the blood. Beyond its effects on LDL, recent studies have reported pleiotropic effects of PCSK9 notably in septic shock, vascular inflammation, viral infection, and cancer. While the functional and structural integrity of peripheral nerves are critically influenced by circulating lipids, the impact of PCSK9 in the peripheral nervous system is unknown. In this study, we investigated the consequences of PCSK9 deficiency on peripheral nerves. We found that PCSK9 deletion in mice leads to peripheral neuropathy characterized by a reduction of thermal and mechanical pain sensations. PCSK9 deficient mice also presented skin structural changes with a reduction of number of terminal nociceptive Schwann cells, Remak fiber axonal swelling, as well as hypomyelination of small nerve fibers. Interestingly, peripheral nerves of PCSK9 deficient mice presented an upregulation of the fatty acid transporter CD36 expression which correlated with an increase in nerve lipid contents and structural mitochondrial abnormalities. Our findings demonstrate that PCSK9 plays a critical role in the peripheral nerves by regulating lipid homeostasis, and its deficiency could lead to the development of symptoms related to peripheral neuropathy. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/583154v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1469ef8org.highwire.dtl.DTLVardef@16ebcd9org.highwire.dtl.DTLVardef@1305cbborg.highwire.dtl.DTLVardef@181758_HPS_FORMAT_FIGEXP M_FIG C_FIG PCSK9 modulates nerve energy metabolism and health. Created with BioRender.com.

neuroscience↗

bioRxiv2023

Metabolic Dependency Shapes Bivalent Antiviral Response in Host Cells: The Role of Glutamine

The establishment of effective antiviral responses within host cells is intricately related to their metabolic status, shedding light on immunometabolism. In this study, we investigated the hypothesis that cellular reliance on glutamine metabolism contributes to the development of a potent antiviral response. We evaluated the antiviral response in the presence or absence of L-glutamine in the culture medium, revealing a bivalent response hinging on cellular metabolism. While certain interferon-stimulated genes (ISGs) exhibited higher expression in an oxidative phosphorylation (OXPHOS)-dependent manner, others were surprisingly upregulated in a glycolytic-dependent manner. This metabolic dichotomy was influenced in part by variations in IFN-{beta} expression. We initially demonstrated that the presence of L-glutamine induced an enhancement of OXPHOS in A549 cells. Furthermore, in cells either stimulated poly:IC or infected with Dengue Virus and Zika Virus, a marked increase in ISGs expression was observed in a dose-dependent manner with L-glutamine supplementation. Interestingly, our findings unveiled a metabolic dependency in the expression of specific ISGs. In particular, genes such as ISG54, ISG12 and ISG15 exhibited heightened expression in cells cultured with L-glutamine, corresponding to higher OXPHOS rates and IFN-{beta} signaling. Conversely, the expression of viperin and 2-5-oligoadenylate synthetase 1 was inversely related to L-glutamine concentration, suggesting a glycolysis-dependent regulation, confirmed by inhibition experiments. This study highlights the intricate interplay between cellular metabolism, especially glutaminergic and glycolytic, and the establishment of the canonical antiviral response characterized by the expression of antiviral effectors, potentially paving the way for novel strategies to modulate antiviral responses through metabolic interventions.

immunology↗