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Neuronal apoptosis drives remodeling states of microglia and shifts in survival pathway dependence [RNA-Seq]

ABSTRACT: Microglia serve critical remodeling roles that shape the developing nervous system, responding to the changing neural environment with phagocytosis or soluble factor secretion. Recent single-cell sequencing (scRNAseq) studies have revealed the context-dependent diversity in microglial properties and gene expression, but the cues promoting this diversity are not well defined. Here, we ask how interactions with apoptotic neurons shape microglial state, including lysosomal and lipid metabolism gene expression and dependence on Colony-stimulating factor 1 receptor (CSF1R) for survival. Using early postnatal mouse retina, a CNS region undergoing significant developmental remodeling, we performed scRNAseq on microglia from mice that are wild-type, lack neuronal apoptosis (Bax KO), or are treated with CSF1R inhibitor (PLX3397). We find that interactions with apoptotic neurons drives multiple microglial remodeling states, subsets of which are resistant to CSF1R inhibition. We find that TAM receptor Mer and complement receptor 3 are required for clearance of apoptotic neurons, but that Mer does not drive expression of remodeling genes. We show TAM receptor Axl is negligible for phagocytosis or remodeling gene expression but is consequential for microglial survival in the absence of CSF1R signaling. Thus, interactions with apoptotic neurons shift microglia towards distinct remodeling states and through Axl, alter microglial dependence on survival pathway, CSF1R.

ORGANISM(S): Mus musculus

PROVIDER: GSE192601 | GEO | 2022/04/27

REPOSITORIES: GEO

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Neuronal apoptosis drives remodeling states of microglia and shifts in survival pathway dependence [scRNA-seq]

Project description:Microglia serve critical remodeling roles that shape the developing nervous system, responding to the changing neural environment with phagocytosis or soluble factor secretion. Recent single-cell sequencing (scRNAseq) studies have revealed the context-dependent diversity in microglial properties and gene expression, but the cues promoting this diversity are not well defined. Here, we ask how interactions with apoptotic neurons shape microglial state, including lysosomal and lipid metabolism gene expression and dependence on Colony-stimulating factor 1 receptor (CSF1R) for survival. Using early postnatal mouse retina, a CNS region undergoing significant developmental remodeling, we performed scRNAseq on microglia from mice that are wild-type, lack neuronal apoptosis (Bax KO), or are treated with CSF1R inhibitor (PLX3397). We find that interactions with apoptotic neurons drives multiple microglial remodeling states, subsets of which are resistant to CSF1R inhibition. We find that TAM receptor Mer and complement receptor 3 are required for clearance of apoptotic neurons, but that Mer does not drive expression of remodeling genes. We show TAM receptor Axl is negligible for phagocytosis or remodeling gene expression but is consequential for microglial survival in the absence of CSF1R signaling. Thus, interactions with apoptotic neurons shift microglia towards distinct remodeling states and through Axl, alter microglial dependence on survival pathway, CSF1R.

2022-04-27 | GSE192600 | GEO

Microglia use TAM receptors to detect and engulf amyloid beta plaques

Project description:Two microglial TAM receptor tyrosine kinases - Axl and Mer - have been linked to Alzheimer’s disease, but their roles in disease have not been tested experimentally. We find that in Alzheimer’s disease and its mouse models, induced expression of Axl and Mer in amyloid plaque-associated microglia is coupled to induced plaque decoration by the TAM ligand Gas6 and its co-ligand phosphatidylserine. In the APP/PS1 mouse model of Alzheimer’s disease, sIngle cell RNAseq analysis comparing wild type microglia with those with Axl and Mer deficiency reveals a similar disease state transitional program of microglia but a dampened differential expression of numerous AD siganture genes in microglia lacking TAM receptors. In line with the transcriptomic data, using two-photon microscopy, we show that genetic ablation of Axl and Mer results in microglia that are unable to normally detect, respond to, organize, or phagocytose amyloid beta plaques. These major deficits notwithstanding, and contrary to expectation, TAM-deficient APP/PS1 mice develop fewer dense-core plaques than APP/PS1 mice with normal microglia. Our findings reveal that the TAM system is an essential mediator of microglial recognition and engulfment of amyloid plaques, and that TAM-driven microglial phagocytosis does not constrain, but rather promotes, plaque development.

2021-02-25 | GSE160523 | GEO

Expression data from knockdown of Tyro3 in hepatocellular carcinoma

Project description:Tyro3 is a member of the TAM (Tyro3, Axl and Mer) receptor family. In this study, we want to know potential association between Tyro3 expression in HCC and the involved signaling pathway.

2018-09-04 | GSE119388 | GEO

Identification of AXL interactome by proximity-dependent protein identification (BioID)

Project description:AXL is a receptor tyrosine kinase (RTK) which, together with TYRO3 and MER, belongs to the TAM receptor family. A ligand for AXL is growth arrest specific 6 (GAS6), which is able to bind all three TAMs with the highest affinity for AXL. AXL is overexpressed in a variety of different cancers, which correlates with poor prognosis, metastasis and drug resistance. However, its biology is still not fully understood and data concerning proteins that interact with this receptor are almost completely lacking. To identify mechanisms underlying the role of GAS6-AXL signaling in cancer, we established an AXL interactome using proximity-dependent biotin identification (BioID) assay. Experiments were conducted in HEK293 cells and human glioblastoma LN229 cells, which do not express and express AXL, respectively. The Gene Ontology (GO) analysis of biological processes indicated enrichment of proteins implicated in cell junction organization, axonogenesis, supramolecular fiber organization, angiogenesis and actin-related processes in bot, non-stimulated and GAS6-stimulated samples. Importantly, in samples with activated AXL, proteins implicated in actin-related processes were overrepresented. Consistent with this, we found that GAS6 stimulation triggered actin remodeling manifested by intense membrane ruffling and macropinocytosis. Our study provides comprehensive data about proteins interacting with AXL. Thus, the obtained results will help to understand the biology of the AXL receptor, particularly with respect to its involvement in cancer invasion.

2021-06-28 | PXD017933 | Pride

The TAM receptor tyrosine kinases Axl and Mer drive the phagocytic differentiation of tissue-resident macrophages

Project description:Many apoptotic thymocytes are generated during the course of T cell selection in the thymus, yet the machinery through which these dead cells are recognized and phagocytically cleared is incompletely understood. We find that the TAM receptor tyrosine kinases Axl and Mer, which are co-expressed by a specialized set of phagocytic thymic macrophages, are essential components of this machinery. Axl-/-Mertk-/- double mutant mice exhibited a marked accumulation of apoptotic cells during the time that autoreactive and nonreactive thymocytes die. Unexpectedly, the double mutants also displayed a profound deficit in the total number of phagocytic macrophages in the thymus, and concomitantly exhibited diminished expression of key non-TAM engulfment systems in the macrophages that remain. These previously unrecognized deficits were not confined to the thymus, and were also evident in the bone marrow and spleen. They had pleiotropic metabolic consequences for the double mutants, which included severe dysregulation of hemoglobin turnover, iron metabolism, and erythropoiesis.

2022-07-12 | GSE192363 | GEO

Compensatory Csf2-driven macrophage activation blunts long-term efficacy of therapeutic Csf1r inhibition in breast-to-brain metastasis

Project description:Tumor microenvironment-targeted therapies are emerging as promising treatment options for different tumor types. Tumor-associated macrophages/microglia (TAMs) represent the most abundant non-malignant cell type in brain metastasis and are known to support metastatic colonization and outgrowth. We used the colony-stimulating factor 1 receptor (Csf1r) inhibitor BLZ945 to target TAMs at distinct stages of the metastatic cascade in experimental breast-to-brain metastasis and demonstrate that Csf1r inhibition leads to anti-tumor responses in prevention and intervention trails. However, compensatory Csf2-mediated pro-inflammatory TAM activation blunts long-term efficacy of Csf1r inhibition by inducing signatures associated with neuroinflammation followed by wound repair responses that foster tumor recurrence. Combined blockade of Csf1r and Csf2rb-Stat5 signaling leads to sustained tumor control and a normalization of microglial activation states.

2019-12-06 | GSE133887 | GEO

single-cell RNA-seq profile of adult microglia under acute Csf1r inhibition and early repopulation

Project description:Microglia are the resident myeloid cell in the central nervous system (CNS). Like other terminally differentiated myeloid cells, microglia rely on Csf1r signaling for survival and maintenance. Surprisingly, a small subset of microglia in the murine brain can survive without Csf1r signaling, as shown in Csf1r KO mice as well as in mice that have been treated with Csf1r inhibitor PLX5622. The nature of such Csf1r independent microglial population has not been fully characterized. Here we applied single-cell RNA-seq to examine the remaining microglia in C57/BL6J mice that were treated with PLX5622 diet (1200 mg/kg, 14 days), which results >90% microglial removal.

2019-12-01 | GSE133773 | GEO

single-cell RNA-seq profile of microglia under acute Csf1r inhibition and early repopulation in adult brain

2020-05-09 | GSE150169 | GEO

Microglia actively remodels adult hippocampal neurogenesis through the phagocytosis secretome

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