MTOR-dependent translation amplifies microglia priming in ageing
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA658992 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12508040_1.fastq.gz | Fastqsanger.gz | |||
| SRR12508040_2.fastq.gz | Fastqsanger.gz | |||
| SRR12508041_1.fastq.gz | Fastqsanger.gz | |||
| SRR12508041_2.fastq.gz | Fastqsanger.gz | |||
| SRR12508042_1.fastq.gz | Fastqsanger.gz |
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Project description:Microglia maintain homeostasis in the brain. However, with age, they become primed and respond more strongly to inflammatory stimuli. We show here that microglia from aged mice upregulated mammalian target of rapamycin (mTOR) complex 1 signaling regulating translation, as well as cytokine protein levels. Genetic ablation of mTOR signaling showed a dual, yet contrasting effect on microglia priming: it caused an NF-kB-dependent upregulation of priming genes at mRNA level; however, mice displayed reduced cytokine protein levels, diminished microglia activation and milder sickness behavior. The effect on translation was dependent on reduced phosphorylation of 4EBP1 and increased 4EBP1 expression, resulting in decreased binding of EIF4E to EIF4G. Similar changes were present in aged human microglia and in damage-associated microglia, indicating upregulation of mTOR-dependent translation is an essential step licensing microglia priming in ageing and neurodegeneration.
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Project description:Microglia maintain homeostasis in the brain. However, with age, they become primed and respond more strongly to inflammatory stimuli. We show here that microglia from aged mice had upregulated mTOR complex 1 signaling controlling translation, as well as protein levels of inflammatory mediators. Genetic ablation of mTOR signaling showed a dual yet contrasting effect on microglia priming: it caused an NF-κB-dependent upregulation of priming genes at the mRNA level; however, mice displayed reduced cytokine protein levels, diminished microglia activation, and milder sickness behavior. The effect on translation was dependent on reduced phosphorylation of 4EBP1, resulting in decreased binding of eIF4E to eIF4G. Similar changes were present in aged human microglia and in damage-associated microglia, indicating that upregulation of mTOR-dependent translation is an essential aspect of microglia priming in aging and neurodegeneration.
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Project description:T cells receive numerous positive and negative signals during primary antigen encounter that control their proliferation and function, but how these signals are integrated to modulate T cell memory has not been fully characterized. In these studies, we demonstrate that combining seemingly opposite signals, CTLA-4 blockade and rapamycin-mediated mTOR inhibition, during in vivo T cell priming leads to both an increase in the frequency of memory CD8+ T cells and improved memory responses to tumors and bacterial challenges. This enhanced efficacy corresponds to increased early expansion and memory precursor differentiation of CD8+ T cells and increased mitochondrial biogenesis and spare respiratory capacity in memory CD8+ T cells in mice treated with anti-CTLA-4 and rapamycin during immunization. Collectively, these results reveal that mTOR inhibition cooperates with rather than antagonizes blockade of CTLA-4, promoting unrestrained effector function and proliferation and an optimal metabolic program for CD8+ T cell memory. Total RNA was isolated from FACS-sorted, antigen-specific CD8+T cells from different treatment conditions at 5 or 35 days after primary T cell activation
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Project description:Rapamycin is a naturally derived macrolide antibiotic that demonstrates immunosuppressive, chemotherapeutic, and anti-ageing effects in model organisms and humans. Importantly, Rapamycin and its analogues are currently used in the clinic against various cancers and neurological disorders. Although Rapamycin is widely perceived as a specific allosteric inhibitor of mTOR (mechanistic target of rapamycin), the master regulator of cellular and organismal physiology, its specificity has not been thoroughly evaluated so far. In fact, previous studies in cells and in mice suggested that Rapamycin may be also acting independently from mTOR to influence various cellular functions. Here, we generated a gene-edited cell line, expressing a Rapamycin-resistant mTOR mutant (mTORRR), and assessed the effects of Rapamycin treatment on the transcriptome and proteome of control and mTORRR-expressing cells. Our data reveal a striking specificity of Rapamycin towards mTOR, demonstrated by virtually no changes in mRNA or protein levels in Rapamycin-treated mTORRR cells, even following prolonged drug treatment. Overall, this study provides the first comprehensive and conclusive assessment of Rapamycin’s specificity, with important potential implications for ageing research and therapeutics.
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