Microglia actively remodels adult hippocampal neurogenesis through the phagocytosis secretome
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ABSTRACT:
PROVIDER: PRJNA532298 | ENA |
REPOSITORIES: ENA
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Project description:During adult hippocampal neurogenesis, the majority of newborn cells undergo apoptosis and are rapidly phagocytosed by resident microglia in order to avoid disturbing the surrounding neurons. Here, we propose that phagocytosis is not merely a passive process of corpse removal but has an active role in maintaining adult hippocampal neurogenesis. First, we found that neurogenesis was disrupted in three defective microglial phagocytosis KO models in vivo (P2Y12, MerTK/Axl , GPR34). We then followed an in vitro approach to perform a transcriptomic analysis of microglial phagocytosis and identified genes involved in metabolism, chromatin remodeling, and neurogenesis-related functions. Finally, we determined that the phagocytic microglia secretome limits the production of new neurons both in vivo and in vitro. Our data suggest that reprogrammed phagocytic microglia acts as a sensor of local cell death, modulating the balance between cell proliferation and cell survival in the neurogenic niche, supporting the long-term maintenance of adult hippocampal neurogenesis.
2020-04-09 | GSE129569 | GEO
Project description: Not available
| S-EPMC7044727 | biostudies-literature
Project description:Oxidative stress is a major risk factor for Alzheimer’s disease (AD), which is characterized by brain atrophy, amyloid plaques, neurofibrillary tangles, and loss of neurons. 8-Oxoguanine, a major oxidatively generated nucleobase highly accumulated in the AD brain, is known to cause neurodegeneration. In mammalian cells, several enzymes play essential roles in minimizing the 8-oxoguanine accumulation in DNA. MUTYH with adenine DNA glycosylase activity excises adenine inserted opposite 8-oxoguanine in DNA. MUTYH is reported to actively contribute to the neurodegenerative process in Parkinson and Huntington diseases and some mouse models of neurodegenerative diseases by accelerating neuronal dysfunction and microgliosis under oxidative conditions; however, whether or not MUTYH is involved in AD pathogenesis remains unclear. In the present study, we examined the contribution of MUTYH to the AD pathogenesis. Using postmortem human brains, we showed that various types of MUTYH transcripts and proteins are expressed in most hippocampal neurons and glia in both non-AD and AD brains. We further introduced MUTYH deficiency into AppNL-G-F/NL-G-F knock-in AD model mice, which produce humanized toxic amyloid-β without the overexpression of APP protein, and investigated the effects of MUTYH deficiency on the behavior, pathology, gene expression, and neurogenesis. MUTYH deficiency improved memory impairment in AppNL-G-F/NL-G-F mice, accompanied by reduced microgliosis. Gene expression profiling strongly suggested that MUTYH is involved in the microglial response pathways under AD pathology and contributes to the phagocytic activity of disease-associated microglia. We also found that MUTYH deficiency ameliorates impaired neurogenesis in the hippocampus, thus improving memory impairment. In conclusion, we propose that MUTYH, which is expressed in the hippocampus of AD patients as well as non-AD subjects, actively contributes to memory impairment by inducing microgliosis with poor neurogenesis in the preclinical AD phase and that MUTYH is a novel therapeutic target for AD, as its deficiency is highly beneficial for ameliorating AD pathogenesis.
2021-12-23 | GSE157766 | GEO
Project description:MUTYH Actively Contributes to Microglial Activation and Impaired Neurogenesis in the Pathogenesis of Alzheimer’s Disease
| PRJNA662708 | ENA
Project description:Apoptosis accounts for ~ 90% of homeostatic cell turnover in the body1. While caspase-dependent apoptosis is known to influence immune tolerance, induction of cell proliferation, and tissue regeneration2-4, how these apoptotic cells contribute to such diverse effects is less understood. Soluble factors released from apoptotic cells could be a means of ‘talking’ to healthy cells in the tissue neighborhood. While a few phagocyte-attracting ‘find-me’ signals released from apoptotic cells are known5, the larger ‘metabolite secretome’ from apoptotic cells is not yet defined. Here, via unbiased profiling of the apoptotic cell secretome, we identified 123 metabolites that are specifically released during apoptosis, while cells still retain membrane integrity. Release of ~25 of these metabolites is dependent on Pannexin 1 (Panx1) channels, which are opened by caspase-dependent cleavage during apoptosis. Interestingly, one of the Panx1-dependent metabolites from apoptotic cells is spermidine, a polyamine whose release could be, in part, due to the continued metabolic activity of dying cells. RNAseq analysis of healthy cells exposed to the apoptotic secretome revealed Panx1-dependent gene programs, including genes linked to suppression of inflammation, cell proliferation, and wound healing. Analysis of the apoptotic secretome across cell types and different apoptotic stimuli, identified a core “set” of 8 Panx1-dependent metabolites. Strikingly, a selected cocktail of these metabolites demonstrated significant immunosuppressive effects by potently reducing disease severity in an inflammatory arthritis model and a lung graft rejection model. Collectively, these data advance the concept that apoptotic cells are not ‘inert’ corpses waiting for removal by phagocytes, but rather they actively communicate with the tissue environment through their metabolite secretome, with implications in tissue inflammation.
2020-03-19 | GSE131906 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE33092: Oncogenic BRAFV600E remodels the melanocyte transcriptome and induces BLNCR1 to regulate melanoma cell migration [HT-seq] GSE37132: Oncogenic BRAFV600E remodels the melanocyte transcriptome and induces BLNCR1 to regulate melanoma cell migration [Affymetrix] Refer to individual Series
2012-04-27 | E-GEOD-37169 | biostudies-arrayexpress
Project description: Not available
| S-EPMC2765197 | biostudies-literature
Project description:We found the bone marrow stromal-derived neural progenitor cells secretome have the neural protection effect. Proteomic analysis was performed nn order to analyze the protection factor in the secretome. Keywords: Neural protection, secretome
2008-10-18 | GSE13242 | GEO
Project description:Inhalation of the amibient air polution ozone causes lung inflammation and can suppress host defense mechanisms, including impairing macrophage phagocytosis. Ozone reacts with cholesterol in the lung to form oxysterols, like secosterol A and secosterol B, which can form covalent adducts on cellular proteins. How oxysterol-protein adduction modifies the function of lung macrophages is unknown. Herein, we used a preoteomic screen to identify lung macrophage proteins that fomr adducts with ozone-derived oxysterols. Analysis show that the phagocytic receptor CD206 and CD64 formed adducts with secosterol A. Adduction of these receptors with ozone-derived oxysterols impaired ligand binding and corresponded with reduced macrophage phagocytosis. This work suggests a novle mechanism for the suppression of macrophage phagocytosis following ozone exposure through the generation of oxysterols and the formation of oxysterol-protein adducts on phagocytic receptors.
2020-07-18 | PXD019317 | Pride