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

作     者：Cristina de Dios Xenia Abadin Vicente Roca-Agujetas Marina Jimenez-Martinez Albert Morales Ramon Trullas Montserrat Mari Anna Colell 

作者机构：Department of Cell Death and ProliferationInstitut d’Investigacions Biomèdiques de BarcelonaConsejo Superior de Investigaciones Científicas(CSIC)Institut d’Investigacions Biomèdiques August Pi I Sunyer(IDIBAPS)BarcelonaSpain Centro de Investigación Biomédica en Red Sobre Enferme-dades Neurodegenerativas(CIBERNED)MadridSpain Department of BiomedicineFaculty of MedicineUniversitat de BarcelonaBarcelonaSpain Present Address:Department of Biochemistry and Molecular BiologyFaculty of PharmacyUniversidad de Sevilla.Instituto de Biomedicina de Sevilla(IBiS)-Hospital Universitario Virgen del Rocío/CSICSevilleSpain Present Address:Department of Clinical Immunology and RheumatologyAmsterdam UMCAmsterdamNetherlands 

出 版 物：《Translational Neurodegeneration》 (转化神经变性病（英文）)

年 卷 期：2023年第12卷第1期

页      面：722-744页

核心收录：

学科分类：1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 10[医学] 

基　　金：supported by MCIN/AEI/10.13039/501100011033 and by“ERDF A way of making Europe”[Grant RTI2018-095572-B-100(A.C.)RTI2018-095672-B-I00(A.M.)and PID2020-115091RB-I00(R.T)] the Instituto de Salud Carlos III[Grant PI19/01410(M.M.)] C.D.was granted with a FPU fellowship(FPU15/01305)from Ministerio de Ciencia,Innovación y Universidades,Spain.X.A is granted with a fellowship(FI21-RH042199)from Agencia de Gestiód’Ajuts Universitaris I de Recerca 

主　　题：Neuroinflammation Mitochondrial oxidative stress Phagocytosis Alzheimer’s disease DAM signature NLRP3 

摘      要：Background Persistent inflammatory response in the brain can lead to tissue damage and *** 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 ***,the mechanisms underlying the sustained activation of inflammasomes in AD are largely *** have previously shown that high brain cholesterol levels promote amyloid-β(Aβ)accumulation and oxidative ***,we investigate whether these cholesterol-mediated changes may regulate the inflam-masome *** SIM-A9 microglia and SH-SY5Y neuroblastoma cells were cholesterol-enriched using a water-soluble cholesterol *** exposure to lipopolysaccharide(LPS)plus muramyl dipeptide or Aβ,activation of the inflammasome pathway was analyzed by immunofluorescence,ELISA and immunoblotting ***-labeled Aβwas employed to monitor changes in microglia *** medium was used to study how microglia-neuron interrelationship modulates the inflammasome-mediated *** In activated microglia,cholesterol enrichment promoted the release of encapsulated IL-1βaccompanied by a switch to a more neuroprotective phenotype,with increased phagocytic capacity and release of neurotrophic *** contrast,in SH-SY5Y cells,high cholesterol levels stimulated inflammasome assembly triggered by both bacterial toxins and Aβpeptides,resulting in GSDMD-mediated ***(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 ***,using conditioned media,we showed that neuronal pyroptosis affects the function of the cholesterol-enriched microglia,lowering its phagocytic activity and,the