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https://www.bilketa.eus/ark:/27020/hal-04183074Achucarro Basque Center for Neuroscience ; Universidad del País Vasco [Espainia] / Euskal Herriko Unibertsitatea [España] = University of the Basque Country [Spain] = Université du pays basque [Espagne] (UPV / EHU)-Ikerbasque - Basque Foundation for ScienceUniversidad del País Vasco / Euskal Herriko Unibertsitatea (UPV / EHU)Instituto de Neurociencias de Castilla y León (INCyL) ; Universidad de Salamanca [España] = University of Salamanca [Spain]Ikerbasque - Basque Foundation for ScienceCentro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) ; Instituto de Salud Carlos III [Madrid] (ISCIII)Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN) ; Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)University of Massachusetts Medical School [Worcester] (UMASS) ; University of Massachusetts System (UMASS)Imagerie et Stratégies Thérapeutiques pour les Cancers et Tissus cérébraux (ISTCT) ; Université de Caen Normandie (UNICAEN) ; Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)Centro de Investigaciones Biológicas Margarita Salas (CIB) ; Consejo Superior de Investigaciones Cientificas [España] = Spanish National Research Council [Spain] (CSIC)Université de Fribourg = University of Fribourg (UNIFR)Universidad de Oviedo = University of OviedoKarolinska University Hospital [Stockholm]Beccari, SolSierra-Torre, VirginiaValero, JorgePereira-Iglesias, MartaGarcía-Zaballa, MikelSoria, Federico, Nde las Heras-Garcia, LauraCarretero-Guillen, AlejandroCapetillo-Zarate, EstibalizDomercq, MariaHuguet, Paloma, RRamonet, DavidOsman, AhmedHan, WeiDominguez, CeciliaFaust, Travis, ETouzani, OmarPampliega, OlatzBoya, PatriciaSchafer, DorothyMariño, GuillermoCanet-Soulas, EmmanuelleBlomgren, KlasPlaza-Zabala, AinhoaSierra, AmandaHAL, hal-041830742023-01-20CERVOXYInternational audienceMicroglial phagocytosis of apoptotic debris prevents buildup damage of neighbor neurons and inflammatory responses. Whereas microglia are very competent phagocytes under physiological conditions, we report their dysfunction in mouse and preclinical monkey models of stroke (macaques and marmosets) by transient occlusion of the medial cerebral artery (tMCAo). By analyzing recently published bulk and single cell RNA sequencing databases, we show that the phagocytosis dysfunc-tion was not explained by transcriptional changes. In contrast, we demonstrate that the impairment of both engulfment and degradation was related to energy depletion triggered by oxygen and nutrient deprivation (OND), which led to reduced process motility, lysosomal exhaustion, and the induction of a protective macroautophagy/autophagy response in microglia. Basal autophagy, in charge of removing and recycling intracellular elements, was critical to maintain microglial physiol-ogy, including survival and phagocytosis, as we determined both in vivo and in vitro using pharma-cological and transgenic approaches. Notably, the autophagy inducer rapamycin partially prevented the phagocytosis impairment induced by tMCAo in vivo but not by OND in vitro, where it even had a detrimental effect on microglia, suggesting that modulating microglial autophagy to optimal levels may be a hard to achieve goal. Nonetheless, our results show that pharmacological interventions, acting directly on microglia or indirectly on the brain environment, have the potential to recover phagocytosis efficiency in the diseased brain. We propose that phagocytosis is a therapeutic target yet to be explored in stroke and other brain disorders and provide evidence that it can be modulated in vivo using rapamycin.https://hal.science/hal-04183074https://normandie-univ.hal.science/hal-04183074v1/file/2022_Beccari_Autophagy.pdfArticle de journal | Aldizkari bateko artikuluavignette : https://www.bilketa.eus/in/rest/Thumb/image?id=ark:/27020/hal-04183074&mat=articleNumenghttp://creativecommons.org/licenses/by-nc-nd/Archive ouverte HAL | HAL artxibo irekiaAutophagyischemialysosomesmicrogliaphagocytosisrapamycinstroketMCAo[SDV]Life Sciences [q-bio]Microglial phagocytosis dysfunction in stroke is driven by energy depletion and induction of autophagy