Microglia Actively Remodel Adult Hippocampal Neurogenesis through the Phagocytosis Secretome
| Autor: | Elena Alberdi, Beáta Sperlágh, Angela Schulz, Irune Diaz-Aparicio, Noelia Rodríguez-Iglesias, Paloma Huguet, Mirjana Maletic-Savatic, Sol Beccari, Oihane Abiega, Jorge Valero, Mar Márquez-Ropero, Ainhoa Plaza-Zabala, Lilla Otrokocsi, Iñaki Paris, Amanda Sierra, Virginia Sierra-Torre, Kaisa E. Happonen, Greg Lemke, Carlos Matute, Irantzu Bernales |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Programmed cell death P2Y12 Phagocytosis Neurogenesis Development/Plasticity/Repair microglia Apoptosis Nerve Tissue Proteins Biology Hippocampal formation Hippocampus 03 medical and health sciences Mice 0302 clinical medicine Downregulation and upregulation Genes Reporter Cell Line Tumor medicine Animals Humans Calcium Signaling MerTK/Axl Research Articles Feedback Physiological Mice Knockout Neurons Microglia c-Mer Tyrosine Kinase General Neuroscience Gene Expression Regulation Developmental MERTK Chromatin Assembly and Disassembly Receptors Purinergic P2Y12 Cell biology Nerve Regeneration Mice Inbred C57BL adult neurogenesis secretome 030104 developmental biology medicine.anatomical_structure Culture Media Conditioned Female Transcriptome Tyrosine kinase 030217 neurology & neurosurgery |
| Zdroj: | The Journal of Neuroscience |
| ISSN: | 1529-2401 |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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