Arg1+ microglia are critical for shaping cognition in female mice
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ABSTRACT:
PROVIDER: PRJNA896130 | ENA |
REPOSITORIES: ENA
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Project description:Here, we describe a microglial subtype characterized by the expression of the enzyme Arginase-1, i.e. Arg1 +microglia.
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Project description:While cognitive impairment is common in peripheral diseases such as chronic kidney disease (CKD), mechanistic insights and effective therapies are lacking. Here, we show that microglial potassium (K+) dyshomeostasis induces noncanonical IL-1β maturation and neuronal dysfunction via IL-1R signaling in CKD. Despite inflammasome activation in the brain, microglial caspase-1 deficiency does not improve inflammation and cognition in CKD mice. Noncanonical IL-1β maturation in microglia is mediated by the cathepsin C–caspase-8 pathway. Restoring K+ homeostasis in microglia or genetically inhibiting neuronal IL-1R1 signaling abolishes CKD-induced cognitive impairment. Microglial K+ dyshomeostasis and noncanonical microglial IL-1β maturation may therefore be druggable targets in some forms of cognitive impairment. These insights identify a new intercellular microglia–neuron crosstalk and identify potential therapeutic targets to combat inflammasome-induced neuronal dysfunction.
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Project description:Microglia (MG) and macrophages (MPs) represent a significant component of the inflammatory response to gliomas. When activated, MG/MP release a variety of pro-inflammatory cytokines, however, they also secrete anti-inflammatory factors that limit their cytotoxic function. The balance between pro and anti-inflammatory functions dictates their antitumor activity. To evaluate potential variations in MG and MP function in gliomas, we isolated these cells (and other Gr1+ cells) from intracranial GL261 murine gliomas by FACS and evaluated their gene expression profiles by microarray analysis. As expected, arginase 1 (Arg1, M2 marker) was highly expressed by tumor-associated Gr1+, MG and MP. However, in contrast to MP and Gr1+ cells that expressed Arg1 shortly after tumor trafficking, Arg1 expression in MG was delayed and occurred in larger tumors. Interestingly, depletion of MPs in tumors did not prevent MG polarization, suggesting direct influence of tumor-specific factors on MG Arg1 upregulation. Finally, Arg1 expression was confirmed in human GBM samples, but most Arg1+ cells were neutrophils and not MPs. These findings confirm variations in tumor MG and MP polarization states and its dependency on tumor microenvironmental factors.
2016-12-31 | GSE77208 | GEO
Project description:Purpose: Microglia are essential for central nervous system (CNS) homeostasis and innate neuroimmune function, and play important roles in neurodegeneration and brain aging. Here, we present gene expression profiles of purified microglia isolated at autopsy from the parietal cortex of 39 human subjects with intact cognition. We identified an age-associated gene signature in human microglia that was enriched for genes involved in cell adhesion, axonal guidance, cell surface receptor expression, and actin disassembly. Methods: mRNA profiles of 39 human microglia samples isolated from subjects with intact cognition, 16 corresponding superior parietal cortex tissue and 10 epilepsy surgical samples were generated in a Illumina HiSEQ 2500 sequencer. mRNA profiles of 6 parietal cortex from mice were prepared with a Quantseq 3’mRNA-Seq kit (Lexogen, USA). Reads were aligned to the hg38 assembly of the human genome using STAR and quantified at the gene level by featureCounts. Differential expression between whole brain tissue, surgical samples and isolated microglia was assessed with limma. Results: Overall, genes expressed by human microglia are similar to those in mouse, including established microglia genes CX3CR1, P2YR12, and ITGAM/CD11B. However, a number of immune genes, not identified as part of the mouse microglial signature, were abundantly expressed in human microglia, including TLR, Fc-gamma and SIGLEC receptors, as well as TAL1 and IFI16, regulators of proliferation and cell cycle. Age-associated changes in human microglia were enriched for genes involved in cell adhesion, axonal guidance, cell surface receptor expression, and actin (dis)assembly. Limited overlap was observed in microglial genes regulated during aging between mice and humans, indicating that human and mouse microglia age differently. Conclusions: Here we present the an extensive human microglia gene expression profile. Critical differences with mouse microglia, especially in the context of aging, were observed which highlight the necessity to independently study human microglia. These data and analyses serve as a starting point to address human-specific microglia genes and functions under physiological and neuropathological conditions.
2017-05-19 | GSE99074 | GEO
Project description:While TGF-β signaling is essential for microglial function, the cellular source of TGF-β ligand and its spatial regulation remains unclear in adult CNS. Our data supports that microglia but not astrocytes or neurons are the primary producers of TGF-β1 ligands needed for microglial homeostasis. Microglia-Tgfb1 KO leads to activation of microglia featuring a dyshomeostatic transcriptomic profile that resembles disease-associated microglia (DAMs), injury-associated microglia, and aged microglia, suggesting that microglial self-produced TGF-β1 ligands are important in the adult CNS. Interestingly, astrocytes in the MG-tgfb1 iKO mice show a transcriptome profile that is closely aligned with A1-like astrocytes. Additionally, using sparse mosaic single cell microglia KO of TGF-β1 ligand we established an autocrine mechanism for TGF-β signaling. Importantly MG-Tgfb1 inducible KO mice show cognitive deficits, supporting that precise spatial regulation of TGF-β1 ligand derived from microglia is critical for the maintenance of brain homeostasis and normal cognitive function in the adult brain.
2023-08-08 | GSE236032 | GEO
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Project description:To determine the contribution at protein levels to the steady state of the cells in different sexes, we estimated the relative amounts of the microglia cells by mass spectrometry-based proteomics approach and further label-free quantification analysis (LFQ). We analysed the differences of protein abundance, comparing the normalized intensity on distinct proteins from four different mice per sex.
2017-11-02 | MSV000081661 | MassIVE
Project description:Noncanonical Il-1β maturation in microglia impairs cognition in chronic kidney disease via neuronal IL1R signaling
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Project description:Brain myeloid cells, include infiltrating macrophages and resident microglia, play an essential role in responding to and inducing neurodegenerative diseases, such as Alzheimer’s disease (AD). Genome-wide association studies (GWAS) implicate many AD casual and risk genes enriched in brain myeloid cells. Coordinated arginine metabolism through arginase 1 (Arg1) is critical for brain myeloid cells to perform biological functions, whereas dysregulated arginine metabolism disrupts them. Altered arginine metabolism is proposed as a new biomarker pathway for AD. We previously reported Arg1 deficiency in myeloid biased cells using lysozyme M (LysM) promoter-driven deletion worsened amyloidosis-related neuropathology and behavioral impairment. However, it remains unclear how Arg1 deficiency in these cells impacts the whole brain to promote amyloidosis. Herein, we aim to determine how Arg1 deficiency driven by LysM restriction during amyloidosis affects fundamental neurodegenerative pathways at the transcriptome level. By applying several bioinformatic tools and analyses, we found that amyloid-β (Aβ) stimulated transcriptomic signatures in autophagy-related pathways and myeloid cells' inflammatory response. At the same time, myeloid Arg1 deficiency during amyloidosis promoted gene signatures of lipid metabolism, myelination, and migration of myeloid cells. Focusing on Aβ associated glial transcriptomic signatures, we found myeloid Arg1 deficiency up-regulated glial gene transcripts that positively correlated with Aβ plaque burden. We also observed that Aβ preferentially activated disease-associated microglial signatures to increase phagocytic response, whereas myeloid Arg1 deficiency selectively promoted homeostatic microglial signature that is non-phagocytic. These transcriptomic findings suggest a critical role for proper Arg1 function during normal and pathological challenges associated with amyloidosis. Furthermore, understanding pathways that govern Arg1 metabolism may provide new therapeutic opportunities to rebalance immune function and improve microglia/macrophage fitness.
2021-04-15 | GSE172108 | GEO
Project description:It is important to maintain cognitive integrity during underwater operations, which may also trigger cognitive alterations. Cognitive effect of underwater operations and the underlying mechanism remain elusive. Here, we found a single underwater operation affects cognition in a time-dependent model. Prolonged exposure elicits significant cognitive impairment and hippocampal dysfunction, which was accompanied by activation of microglia and upregulation of pro-inflammatory cytokines. RNA-sequencing supported the involvement of neuroinflammation and indicated the critical role of CCR3. Knockdown of CCR3 significantly rescued cognitive impairment and hippocampal dysfunction. Furthermore, the upregulation of pro-inflammatory cytokines was also reversed. Mechanistically, CCR3 knockdown switched the activated microglia from a pro-inflammatory to neuroprotective phenotype. Taken together, these results highlighted the time-dependent effects of a single underwater operation on cognitive function. Knocking down CCR3 can attenuate neuroinflammation by regulating polarization of activated microglia, thereby alleviating prolonged underwater operation-induced cognitive impairment.
2024-05-20 | GSE247651 | GEO