Inflammasome activation under high cholesterol load triggers a protective microglial phenotype while promoting neuronal pyroptosis

Translational Neurodegeneration

Research

Montserrat Mari¹  Xenia Abadin¹  Albert Morales¹  Ramon Trullas²  Anna Colell²  Vicente Roca-Agujetas³  Cristina de Dios⁴  Marina Jimenez-Martinez⁵ 

[1] Department of Cell Death and Proliferation, Institut d’Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain;Department of Cell Death and Proliferation, Institut d’Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain;Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain;Department of Cell Death and Proliferation, Institut d’Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain;Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain;Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Universidad de Sevilla., Instituto de Biomedicina de Sevilla (IBiS)-Hospital Universitario Virgen del Rocío/CSIC, Seville, Spain;Department of Cell Death and Proliferation, Institut d’Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain;Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain;Department of Biomedicine, Faculty of Medicine, Universitat de Barcelona, Barcelona, Spain;Department of Cell Death and Proliferation, Institut d’Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain;Department of Clinical Immunology and Rheumatology, Amsterdam UMC, Amsterdam, Netherlands;

关键词: Neuroinflammation;    Mitochondrial oxidative stress;    Phagocytosis;    Alzheimer’s disease;    DAM signature;    NLRP3;   

DOI  :  10.1186/s40035-023-00343-3

 received in 2022-08-31, accepted in 2023-02-16,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundPersistent inflammatory response in the brain can lead to tissue damage and neurodegeneration. In Alzheimer's disease (AD), there is an aberrant activation of inflammasomes, molecular platforms that drive inflammation through caspase-1-mediated proteolytic cleavage of proinflammatory cytokines and gasdermin D (GSDMD), the executor of pyroptosis. However, the mechanisms underlying the sustained activation of inflammasomes in AD are largely unknown. We have previously shown that high brain cholesterol levels promote amyloid-β (Aβ) accumulation and oxidative stress. Here, we investigate whether these cholesterol-mediated changes may regulate the inflammasome pathway.MethodsSIM-A9 microglia and SH-SY5Y neuroblastoma cells were cholesterol-enriched using a water-soluble cholesterol complex. After exposure to lipopolysaccharide (LPS) plus muramyl dipeptide or Aβ, activation of the inflammasome pathway was analyzed by immunofluorescence, ELISA and immunoblotting analysis. Fluorescently-labeled Aβ was employed to monitor changes in microglia phagocytosis. Conditioned medium was used to study how microglia-neuron interrelationship modulates the inflammasome-mediated response.ResultsIn activated microglia, cholesterol enrichment promoted the release of encapsulated IL-1β accompanied by a switch to a more neuroprotective phenotype, with increased phagocytic capacity and release of neurotrophic factors. In contrast, in SH-SY5Y cells, high cholesterol levels stimulated inflammasome assembly triggered by both bacterial toxins and Aβ peptides, resulting in GSDMD-mediated pyroptosis. Glutathione (GSH) ethyl ester treatment, which recovered the cholesterol-mediated depletion of mitochondrial GSH levels, significantly reduced the Aβ-induced oxidative stress in the neuronal cells, resulting in lower inflammasome activation and cell death. Furthermore, using conditioned media, we showed that neuronal pyroptosis affects the function of the cholesterol-enriched microglia, lowering its phagocytic activity and, therefore, the ability to degrade extracellular Aβ.ConclusionsChanges in intracellular cholesterol levels differentially regulate the inflammasome-mediated immune response in microglia and neuronal cells. Given the microglia-neuron cross-talk in the brain, cholesterol modulation should be considered a potential therapeutic target for AD treatment, which may help to block the aberrant and chronic inflammation observed during the disease progression.

【 授权许可】

CC BY   
© The Author(s) 2023

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