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Radiotherapy induces persistent innate immune reprogramming of microglia into a priming state

ABSTRACT: Radiotherapy induces persistent innate immune reprogramming of microglia into a priming state

PROVIDER: PRJNA956850 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24204012_1.fastq.gz	Fastqsanger.gz
	SRR24204012_2.fastq.gz	Fastqsanger.gz
	SRR24204013_1.fastq.gz	Fastqsanger.gz
	SRR24204013_2.fastq.gz	Fastqsanger.gz
	SRR24204014_1.fastq.gz	Fastqsanger.gz

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Radiotherapy induces persistent innate immune reprogramming of microglia into a priming state

Project description:More than half of all brain tumour survivors experience debilitating and often progressive cognitive decline after treatment with radiotherapy. Microglia, the tissue-resident macrophages of the brain, have been implicated in this decline. In response to various insults microglia can develop innate immune memory (IMM), which can either enhance (priming) or repress (tolerance) the response to subsequent inflammatory challenges. Here, we investigated whether radiation can affect the IMM of microglia by irradiating the brains of rats and later exposing them to a second inflammatory challenge. Transcriptomic profiling of microglia isolated from irradiated rats showed a stronger immune response to a second inflammatory insult demonstrating that radiation can lead to long-lasting molecular reprogramming of microglia. Transcriptomic analysis of post-mortem non-tumour brain tissue of glioblastoma patients indicates that radiation-induced microglial priming is conserved in humans. Targeting microglial priming after radiotherapy or avoiding further inflammatory insults could decrease progressive radiotherapy-induced cognitive decline.

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mTOR-dependent translation amplifies microglia priming in ageing

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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Persistent changes in nociceptor translatomes govern hyperalgesic priming in mouse models

Project description:Hyperalgesic priming is a model system that has been widely used to understand plasticity in painful stimulus-detecting sensory neurons, called nociceptors. A key feature of this model system is that following priming, stimuli that do not normally cause hyperalgesia now readily provoke this state. We hypothesized that hyperalgesic priming occurs due to reorganization of translation of mRNA in nociceptors. To test this hypothesis we used paclitaxel treatment as the priming stimulus and translating ribosome affinity purification (TRAP) to measure persistent changes in mRNA translation in Nav1.8+ nociceptors. TRAP sequencing revealed 161 genes with persistently altered mRNA translation in the primed state. We identified Gpr88as upregulated, and Metrn as downregulated. We confirmed a functional role for these genes wherein a GPR88 agonist causes pain only in primed mice, and established hyperalgesic priming is reversed by Meteorin. Our work demonstrates that altered nociceptor translatomes are causative in producing hyperalgesic priming.

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mTOR-dependent translation amplifies microglia priming in ageing

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Transcriptional regulation of microglia priming by IRF7, IRF9 and SMAD3 in accelerated aging mice [ATAC-seq]

Project description:Microglia are the tissue resident macrophages of the central nervous system (CNS). Dysregulation of inflammatory processes in the CNS is associated with aging, and neurodegenerative diseases, where microglia acquire a sensitized, or primed, phenotype, which is characterized by an increased inflammatory phenotype and an exaggerated reactivity to immune challenges. Transcriptomic profiling of microglia in different neurodegenerative disease and aging mouse models identified a common, primed, gene expression signature. However, the transcriptional mechanisms that mediate microglia priming still remains unclear. In DNA repair deficient (Ercc1Δ/ko) mice, microglia acquire a profound primed phenotype and by integrating RNA-seq and ATAC-seq data of Ercc1Δ/ko microglia, we identified transcription factors IRF7, IRF9 and SMAD3 as possible core regulators of microglia priming. Our data suggest that increased IRF7/IRF9 activity and decreased SMAD3 activity might be important for microglia to acquire a primed gene signature. This study provides insight in the transcriptomic regulation of primed microglia, which are implicated in aging and neurodegenerative diseases.

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Transcriptional regulation of microglia priming by IRF7, IRF9 and SMAD3 in accelerated aging mice [RNA-seq]

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Persistent changes in nociceptor translatomes govern hyperalgesic priming in mouse models

Project description:Persistent changes in nociceptor translatomes govern hyperalgesic priming in mouse models

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2022-12-31 | GSE212248 | GEO

miRNA profiling of primary breast cancers from patients treated with radiotherapy

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