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J Neurosci. 2020 Feb 12;40(7):1453-1482. doi: 10.1523/JNEUROSCI.0993-19.2019. Epub 2020 Jan 2.

Microglia Actively Remodel Adult Hippocampal Neurogenesis through the Phagocytosis Secretome.

Author information

1
Achucarro Basque Center for Neuroscience, Leioa, Bizkaia 48940, Spain.
2
University of the Basque Country UPV/EHU, Leioa, Bizkaia 48940, Spain.
3
Rudolf-Schönheimer-Institute of Biochemistry, Medical Faculty, University Leipzig 04109, Germany.
4
Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary.
5
Molecular Neurobiology Laboratory.
6
Immunobiology and Microbial Pathogenesis Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037.
7
Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030.
8
Department of Pediatrics and Neuroscience, Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, and.
9
Achucarro Basque Center for Neuroscience, Leioa, Bizkaia 48940, Spain, amanda.sierra@achucarro.org jorge.valero@achucarro.org.
10
Ikerbasque Foundation, Bilbao, Bizkaia 48013, Spain.

Abstract

During adult hippocampal neurogenesis, most newborn cells undergo apoptosis and are rapidly phagocytosed by resident microglia to prevent the spillover of intracellular contents. Here, we propose that phagocytosis is not merely passive corpse removal but has an active role in maintaining neurogenesis. First, we found that neurogenesis was disrupted in male and female mice chronically deficient for two phagocytosis pathways: the purinergic receptor P2Y12, and the tyrosine kinases of the TAM family Mer tyrosine kinase (MerTK)/Axl. In contrast, neurogenesis was transiently increased in mice in which MerTK expression was conditionally downregulated. Next, we performed a transcriptomic analysis of the changes induced by phagocytosis in microglia in vitro and identified genes involved in metabolism, chromatin remodeling, and neurogenesis-related functions. Finally, we discovered that the secretome of phagocytic microglia limits the production of new neurons both in vivo and in vitro Our data suggest that microglia act as a sensor of local cell death, modulating the balance between proliferation and survival in the neurogenic niche through the phagocytosis secretome, thereby supporting the long-term maintenance of adult hippocampal neurogenesis.SIGNIFICANCE STATEMENT Microglia are the brain professional phagocytes and, in the adult hippocampal neurogenic niche, they remove newborn cells naturally undergoing apoptosis. Here we show that phagocytosis of apoptotic cells triggers a coordinated transcriptional program that alters their secretome, limiting neurogenesis both in vivo and in vitro In addition, chronic phagocytosis disruption in mice deficient for receptors P2Y12 and MerTK/Axl reduces adult hippocampal neurogenesis. In contrast, inducible MerTK downregulation transiently increases neurogenesis, suggesting that microglial phagocytosis provides a negative feedback loop that is necessary for the long-term maintenance of adult hippocampal neurogenesis. Therefore, we speculate that the effects of promoting engulfment/degradation of cell debris may go beyond merely removing corpses to actively promoting regeneration in development, aging, and neurodegenerative diseases.

KEYWORDS:

MerTK/Axl; P2Y12; adult neurogenesis; microglia; phagocytosis; secretome

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