Microglial phagocytosis dysfunction in stroke is driven by energy depletion and induction of autophagy.

Autor: Beccari S; Glial Cell Biology Labb, Department of Biochemistry and Molecular Biology, Achucarro Basque Center for Neuroscience, 48940, Leioa, Bizkaia, Spain.; Department of Neuroscience, University of the Basque Country UPV/EHU, 48940, Leioa, Bizkaia, Spain., Sierra-Torre V; Glial Cell Biology Labb, Department of Biochemistry and Molecular Biology, Achucarro Basque Center for Neuroscience, 48940, Leioa, Bizkaia, Spain.; Department of Neuroscience, University of the Basque Country UPV/EHU, 48940, Leioa, Bizkaia, Spain., Valero J; Glial Cell Biology Labb, Department of Biochemistry and Molecular Biology, Achucarro Basque Center for Neuroscience, 48940, Leioa, Bizkaia, Spain.; Department of Neuroscience, University of the Basque Country UPV/EHU, 48940, Leioa, Bizkaia, Spain.; Neural Plasticity and Neurorepair Group, Laboratory of Neuronal Plasticity and Neurorepair, Institute for Neuroscience of Castilla y León (INCyL), and Institute for Biomedical Research of Salamanca, University of Salamanca, 37007, Salamanca, Spain., Pereira-Iglesias M; Glial Cell Biology Labb, Department of Biochemistry and Molecular Biology, Achucarro Basque Center for Neuroscience, 48940, Leioa, Bizkaia, Spain.; Department of Neuroscience, University of the Basque Country UPV/EHU, 48940, Leioa, Bizkaia, Spain., García-Zaballa M; Glial Cell Biology Labb, Department of Biochemistry and Molecular Biology, Achucarro Basque Center for Neuroscience, 48940, Leioa, Bizkaia, Spain.; Department of Neuroscience, University of the Basque Country UPV/EHU, 48940, Leioa, Bizkaia, Spain., Soria FN; Glial Cell Biology Labb, Department of Biochemistry and Molecular Biology, Achucarro Basque Center for Neuroscience, 48940, Leioa, Bizkaia, Spain.; Department of Neuroscience, University of the Basque Country UPV/EHU, 48940, Leioa, Bizkaia, Spain.; Ikerbasque Foundation, 48009, Bilbao, Bizkaia, Spain., De Las Heras-Garcia L; Glial Cell Biology Labb, Department of Biochemistry and Molecular Biology, Achucarro Basque Center for Neuroscience, 48940, Leioa, Bizkaia, Spain.; Department of Neuroscience, University of the Basque Country UPV/EHU, 48940, Leioa, Bizkaia, Spain., Carretero-Guillen A; Glial Cell Biology Labb, Department of Biochemistry and Molecular Biology, Achucarro Basque Center for Neuroscience, 48940, Leioa, Bizkaia, Spain., Capetillo-Zarate E; Glial Cell Biology Labb, Department of Biochemistry and Molecular Biology, Achucarro Basque Center for Neuroscience, 48940, Leioa, Bizkaia, Spain.; Department of Neuroscience, University of the Basque Country UPV/EHU, 48940, Leioa, Bizkaia, Spain.; Ikerbasque Foundation, 48009, Bilbao, Bizkaia, Spain.; Centro de Investigación en Red de Enfermedades Neurodegenerativas (CIBERNED), Spain., Domercq M; Glial Cell Biology Labb, Department of Biochemistry and Molecular Biology, Achucarro Basque Center for Neuroscience, 48940, Leioa, Bizkaia, Spain.; Department of Neuroscience, University of the Basque Country UPV/EHU, 48940, Leioa, Bizkaia, Spain., Huguet PR; Glial Cell Biology Labb, Department of Biochemistry and Molecular Biology, Achucarro Basque Center for Neuroscience, 48940, Leioa, Bizkaia, Spain.; Department of Neuroscience, University of the Basque Country UPV/EHU, 48940, Leioa, Bizkaia, Spain., Ramonet D; INSERM U1060 CarMeN, Université Claude Bernard Lyon 1 - IRIS team, CarMeN, bat. B13, gpt hosp. Est, 59 bld Pinel, 69500, Bron, Auvergne-Rhône-Alpes, France., Osman A; Department of Women and Children´s Health, Karolisnka Institute, 17164, Stockholm, Södermanland and Uppland, Sweden., Han W; Department of Women and Children´s Health, Karolisnka Institute, 17164, Stockholm, Södermanland and Uppland, Sweden., Dominguez C; Department of Women and Children´s Health, Karolisnka Institute, 17164, Stockholm, Södermanland and Uppland, Sweden., Faust TE; Department of Neurobiology, University of Massachusetts Medical School, 01605, Worcester, MA, USA., Touzani O; Normandie-Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, 14000, Caen, Normandie, France., Pampliega O; Glial Cell Biology Labb, Department of Biochemistry and Molecular Biology, Achucarro Basque Center for Neuroscience, 48940, Leioa, Bizkaia, Spain.; Department of Neuroscience, University of the Basque Country UPV/EHU, 48940, Leioa, Bizkaia, Spain., Boya P; Laboratory of Autophagy, Centro de Investigaciones Biológicas Margarita Salas, Madrid 28040, Spain.; Department of Medicine, University of Fribourg, 1700, Freiburg, Switzerland., Schafer D; Department of Neurobiology, University of Massachusetts Medical School, 01605, Worcester, MA, USA., Mariño G; Department of Medicine, University of Fribourg, 1700, Freiburg, Switzerland.; Department of Functional Biology, University of Oviedo, 33003, Oviedo, Asturias, Spain., Canet-Soulas E; INSERM U1060 CarMeN, Université Claude Bernard Lyon 1 - IRIS team, CarMeN, bat. B13, gpt hosp. Est, 59 bld Pinel, 69500, Bron, Auvergne-Rhône-Alpes, France., Blomgren K; Department of Women and Children´s Health, Karolisnka Institute, 17164, Stockholm, Södermanland and Uppland, Sweden.; Department of Pediatric Oncology, Karolinska University Hospital, 171 64, Stockholm, Södermanland and Uppland, Sweden., Plaza-Zabala A; Glial Cell Biology Labb, Department of Biochemistry and Molecular Biology, Achucarro Basque Center for Neuroscience, 48940, Leioa, Bizkaia, Spain.; Department of Pharmacology, University of the Basque Country UPV/EHU, 48940, Leioa, Bizkaia, Spain., Sierra A; Glial Cell Biology Labb, Department of Biochemistry and Molecular Biology, Achucarro Basque Center for Neuroscience, 48940, Leioa, Bizkaia, Spain.; Department of Neuroscience, University of the Basque Country UPV/EHU, 48940, Leioa, Bizkaia, Spain.; Ikerbasque Foundation, 48009, Bilbao, Bizkaia, Spain.
Jazyk: angličtina
Zdroj: Autophagy [Autophagy] 2023 Jul; Vol. 19 (7), pp. 1952-1981. Date of Electronic Publication: 2023 Jan 20.
DOI: 10.1080/15548627.2023.2165313
Abstrakt: Microglial 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 dysfunction 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 physiology, including survival and phagocytosis, as we determined both in vivo and in vitro using pharmacological 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. Abbreviations: AIF1/IBA1: allograft inflammatory factor 1; AMBRA1: autophagy/beclin 1 regulator 1; ATG4B: autophagy related 4B, cysteine peptidase; ATP: adenosine triphosphate; BECN1: beclin 1, autophagy related; CASP3: caspase 3; CBF: cerebral blood flow; CCA: common carotid artery; CCR2: chemokine (C-C motif) receptor 2; CIR: cranial irradiation; Csf1r/v-fms : colony stimulating factor 1 receptor; CX3CR1: chemokine (C-X3-C motif) receptor 1; DAPI: 4',6-diamidino-2-phenylindole; DG: dentate gyrus; GO: Gene Ontology; HBSS: Hanks' balanced salt solution; HI: hypoxia-ischemia; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MCA: medial cerebral artery; MTOR: mechanistic target of rapamycin kinase; OND: oxygen and nutrient deprivation; Ph/A coupling: phagocytosis-apoptosis coupling; Ph capacity: phagocytic capacity; Ph index: phagocytic index; SQSTM1: sequestosome 1; RNA-Seq: RNA sequencing; TEM: transmission electron microscopy; tMCAo: transient medial cerebral artery occlusion; ULK1: unc-51 like kinase 1.
Databáze: MEDLINE
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