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Neuronal hyperactivity disturbs ATP microgradients, impairs microglial motility, and reduces phagocytic receptor expression triggering apoptosis/microglial phagocytosis uncoupling

Neuronal hyperactivity disturbs ATP microgradients, impairs microglial motility, and reduces phagocytic receptor expression triggering apoptosis/microglial phagocytosis uncoupling
Neuronal hyperactivity disturbs ATP microgradients, impairs microglial motility, and reduces phagocytic receptor expression triggering apoptosis/microglial phagocytosis uncoupling
Phagocytosis is essential to maintain tissue homeostasis in a large number of inflammatory and autoimmune diseases, but its role in the diseased brain is poorly explored. Recent findings suggest that in the adult hippocampal neurogenic niche, where the excess of newborn cells undergo apoptosis in physiological conditions, phagocytosis is efficiently executed by surveillant, ramified microglia. To test whether microglia are efficient phagocytes in the diseased brain as well, we confronted them with a series of apoptotic challenges and discovered a generalized response. When challenged with excitotoxicity in vitro (via the glutamate agonist NMDA) or inflammation in vivo (via systemic administration of bacterial lipopolysaccharides or by omega 3 fatty acid deficient diets), microglia resorted to different strategies to boost their phagocytic efficiency and compensate for the increased number of apoptotic cells, thus maintaining phagocytosis and apoptosis tightly coupled. Unexpectedly, this coupling was chronically lost in a mouse model of mesial temporal lobe epilepsy (MTLE) as well as in hippocampal tissue resected from individuals with MTLE, a major neurological disorder characterized by seizures, excitotoxicity, and inflammation. Importantly, the loss of phagocytosis/apoptosis coupling correlated with the expression of microglial proinflammatory, epileptogenic cytokines, suggesting its contribution to the pathophysiology of epilepsy. The phagocytic blockade resulted from reduced microglial surveillance and apoptotic cell recognition receptor expression and was not directly mediated by signaling through microglial glutamate receptors. Instead, it was related to the disruption of local ATP microgradients caused by the hyperactivity of the hippocampal network, at least in the acute phase of epilepsy. Finally, the uncoupling led to an accumulation of apoptotic newborn cells in the neurogenic niche that was due not to decreased survival but to delayed cell clearance after seizures. These results demonstrate that the efficiency of microglial phagocytosis critically affects the dynamics of apoptosis and urge to routinely assess the microglial phagocytic efficiency in neurodegenerative disorders.
1544-9173
1-48
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Laye, S.
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Matute, C.
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Abiega, O., Beccari, S., Diaz-Aparicio, I., Nadjar, A., Laye, S., Leyrolle, Q., Gomez-Nicola, D., Domercq, M., Perez-Samartin, A., Sanchez-Zafra, V., Paris, I., Valero, J., Savage, J.C., Hui, C.W., Tremblay, M.E., Deudero, J.J.P., Brewster, A.L., Anderson, A.E., Zaldumbide, L., Galbarriatu, L., Marinas, A., Vivanco, M.D.M., Matute, C., Maletic-Savatic, M., Encinas, J.M. and Sierra, A. (2016) Neuronal hyperactivity disturbs ATP microgradients, impairs microglial motility, and reduces phagocytic receptor expression triggering apoptosis/microglial phagocytosis uncoupling. PLoS Biology, 14 (5), 1-48. (doi:10.1371/journal.pbio.1002466).

Record type: Article

Abstract

Phagocytosis is essential to maintain tissue homeostasis in a large number of inflammatory and autoimmune diseases, but its role in the diseased brain is poorly explored. Recent findings suggest that in the adult hippocampal neurogenic niche, where the excess of newborn cells undergo apoptosis in physiological conditions, phagocytosis is efficiently executed by surveillant, ramified microglia. To test whether microglia are efficient phagocytes in the diseased brain as well, we confronted them with a series of apoptotic challenges and discovered a generalized response. When challenged with excitotoxicity in vitro (via the glutamate agonist NMDA) or inflammation in vivo (via systemic administration of bacterial lipopolysaccharides or by omega 3 fatty acid deficient diets), microglia resorted to different strategies to boost their phagocytic efficiency and compensate for the increased number of apoptotic cells, thus maintaining phagocytosis and apoptosis tightly coupled. Unexpectedly, this coupling was chronically lost in a mouse model of mesial temporal lobe epilepsy (MTLE) as well as in hippocampal tissue resected from individuals with MTLE, a major neurological disorder characterized by seizures, excitotoxicity, and inflammation. Importantly, the loss of phagocytosis/apoptosis coupling correlated with the expression of microglial proinflammatory, epileptogenic cytokines, suggesting its contribution to the pathophysiology of epilepsy. The phagocytic blockade resulted from reduced microglial surveillance and apoptotic cell recognition receptor expression and was not directly mediated by signaling through microglial glutamate receptors. Instead, it was related to the disruption of local ATP microgradients caused by the hyperactivity of the hippocampal network, at least in the acute phase of epilepsy. Finally, the uncoupling led to an accumulation of apoptotic newborn cells in the neurogenic niche that was due not to decreased survival but to delayed cell clearance after seizures. These results demonstrate that the efficiency of microglial phagocytosis critically affects the dynamics of apoptosis and urge to routinely assess the microglial phagocytic efficiency in neurodegenerative disorders.

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Accepted/In Press date: 21 April 2016
e-pub ahead of print date: 26 May 2016
Published date: 27 May 2016
Organisations: Biomedicine

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Local EPrints ID: 395561
URI: https://eprints.soton.ac.uk/id/eprint/395561
ISSN: 1544-9173
PURE UUID: b0c00c07-f1d9-405e-acb5-edd8d8d051e4
ORCID for D. Gomez-Nicola: ORCID iD orcid.org/0000-0002-5316-2682

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Date deposited: 01 Jun 2016 12:56
Last modified: 06 Jun 2018 12:33

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Contributors

Author: O. Abiega
Author: S. Beccari
Author: I. Diaz-Aparicio
Author: A. Nadjar
Author: S. Laye
Author: Q. Leyrolle
Author: D. Gomez-Nicola ORCID iD
Author: M. Domercq
Author: A. Perez-Samartin
Author: V. Sanchez-Zafra
Author: I. Paris
Author: J. Valero
Author: J.C. Savage
Author: C.W. Hui
Author: M.E. Tremblay
Author: J.J.P. Deudero
Author: A.L. Brewster
Author: A.E. Anderson
Author: L. Zaldumbide
Author: L. Galbarriatu
Author: A. Marinas
Author: M.D.M. Vivanco
Author: C. Matute
Author: M. Maletic-Savatic
Author: J.M. Encinas
Author: A. Sierra

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