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Effects of long-term and brain-wide colonization of peripheral bone marrow-derived myeloid cells in the CNS

ABSTRACT: Effects of long-term and brain-wide colonization of peripheral bone marrow-derived myeloid cells in the CNS

PROVIDER: PRJNA662084 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12604400_1.fastq.gz	Fastqsanger.gz
	SRR12604400_2.fastq.gz	Fastqsanger.gz
	SRR12604401_1.fastq.gz	Fastqsanger.gz
	SRR12604401_2.fastq.gz	Fastqsanger.gz
	SRR12604402_1.fastq.gz	Fastqsanger.gz

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Effects of long-term and brain-wide colonization of peripheral bone marrow-derived myeloid cells in the CNS.

Project description:BackgroundMicroglia, the primary resident myeloid cells of the brain, play critical roles in immune defense by maintaining tissue homeostasis and responding to injury or disease. However, microglial activation and dysfunction has been implicated in a number of central nervous system (CNS) disorders, thus developing tools to manipulate and replace these myeloid cells in the CNS is of therapeutic interest.MethodsUsing whole body irradiation, bone marrow transplant, and colony-stimulating factor 1 receptor inhibition, we achieve long-term and brain-wide (~ 80%) engraftment and colonization of peripheral bone marrow-derived myeloid cells (i.e., monocytes) in the brain parenchyma and evaluated the long-term effects of their colonization in the CNS.ResultsHere, we identify a monocyte signature that includes an upregulation in Ccr1, Ms4a6b, Ms4a6c, Ms4a7, Apobec1, Lyz2, Mrc1, Tmem221, Tlr8, Lilrb4a, Msr1, Nnt, and Wdfy1 and a downregulation of Siglech, Slc2a5, and Ccl21a/b. We demonstrate that irradiation and long-term (~ 6 months) engraftment of the CNS by monocytes induces brain region-dependent alterations in transcription profiles, astrocytes, neuronal structures, including synaptic components, and cognition. Although our results show that microglial replacement with peripherally derived myeloid cells is feasible and that irradiation-induced changes can be reversed by the replacement of microglia with monocytes in the hippocampus, we also observe that brain-wide engraftment of peripheral myeloid cells (relying on irradiation) can result in cognitive and synaptic deficits.ConclusionsThese findings provide insight into better understanding the role and complexity of myeloid cells in the brain, including their regulation of other CNS cells and functional outcomes.

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Effects of long-term and brain-wide colonization of peripheral bone marrow-derived myeloid cells in the CNS

Project description:This dataset allows for the exploration of irradiation and long-term monocyte engraftment on gene expression in wild-type (C57/BL6) mice, across multiple brain regions.

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Project description:Rheumatoid arthritis (RA) is linked to depression and dementia in later life by inflammatory involvement of the central nervous system (CNS). Regional heterogeneity of brain immunophenotypes was described under homeostasis, but a topographical resolution of CNS immune responses in chronic peripheral inflammatory diseases like RA is missing. We demonstrate regional heterogeneity of CNS susceptibility to chronic peripheral inflammation in the human tumor necrosis factor α transgenic (TNFtg) mouse model of RA. TNFtg mice showed myeloid cell infiltration, microglial activation, and a mutual transcriptomic fingerprint of neuroinflammation in the cortex, striatum, and thalamus. Immune responses were minimal in the hippocampus and cerebellum. We demonstrate regional CNS immune responses to chronic peripheral inflammation, sparing the hippocampus and cerebellum and reversible by peripheral anti-inflammatory treatment. Targeting microenvironmental susceptibility or resilience of brain regions will help to prevent and treat RA-related neuropsychiatric comorbidity. RNA-sequencing was performed from five brain regions (cortex, striatum, thalamus, hippocampus, and cerebellum) from C57Bl6/J wild type mice and TNFtg mice (strain Tg197; kindly provided by George Kollias (Fleming Institute, Vari, Greece).

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