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Microglia actively remodel adult hippocampal neurogenesis through the phagocytosis secretome

Diaz-Aparicio, Irune and Paris, Iñaki and Sierra-Torre, Virginia and Plaza-Zabala, Ainhoa and Rodríguez-Iglesias, Noelia and Bereczkiné Otrokocsi, Lilla and Sperlágh, Beáta (2020) Microglia actively remodel adult hippocampal neurogenesis through the phagocytosis secretome. JOURNAL OF NEUROSCIENCE, 40 (7). pp. 1453-1482. ISSN 0270-6474

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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 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 STATEMENTMicroglia 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, ageing, and neurodegenerative diseases.

Item Type: Article
Uncontrolled Keywords: Adult neurogenesis; MerTK/Axl;
Subjects: R Medicine / orvostudomány > R1 Medicine (General) / orvostudomány általában
SWORD Depositor: MTMT SWORD
Depositing User: MTMT SWORD
Date Deposited: 11 Mar 2021 13:49
Last Modified: 11 Mar 2021 13:49
URI: http://real.mtak.hu/id/eprint/122151

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