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| Status |
Public on Mar 01, 2024 |
| Title |
Circulating senescent myeloid cells drive blood brain barrier breakdown and neurodegeneration |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Neurodegenerative diseases (ND) are characterized by a progressive loss of neuronal function. Mechanisms of ND pathogenesis are incompletely understood hampering the development of effective therapies. Langerhans cell histiocytosis (LCH) is an inflammatory neoplastic disorder caused by hematopoietic progenitors expressing MAPK activating mutations that differentiate into senescent dendritic cells that drive formation of lesions. Some patients with systemic LCH subsequently develop progressive and incurable neurodegeneration (LCH-ND). Here, we show that LCH-ND is caused by hematopoietic cells that are clonal with systemic LCH lesion histiocytes. Strikingly, we discovered that circulating BRAFV600E+ myeloid cells cause the breakdown of the blood-brain barrier (BBB), enabling migration of into the brain where they differentiate into senescent, inflammatory macrophages that accumulate in the brainstem and cerebellum. Blocking MAPK activity and senescence programs synergistically reduced parenchymal infiltration, neuroinflammation and neurologic damage in preclinical LCH-ND. MAPK activation in circulating myeloid cells represents a novel and targetable mechanism of ND.
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| |
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| Overall design |
Comparative gene expression profiling analysis of RNA-seq data for sorted myeloid cells from BRAFV600E WT and mutant mice.
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| |
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| Contributor(s) |
Park MD, Wilk CM |
| Citation(s) |
38091952 |
| |
| Submission date |
Mar 22, 2023 |
| Last update date |
Jan 29, 2025 |
| Contact name |
MATTHEW Dae-Young PARK |
| E-mail(s) |
matthew.park@icahn.mssm.edu
|
| Phone |
2024000082
|
| Organization name |
Icahn School of Medicine at Mount Sinai
|
| Street address |
50 East 98th Street, 6A-1
|
| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10029 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
|
| Samples (6)
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| Relations |
| BioProject |
PRJNA947622 |
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