1. Circulating senescent myeloid cells infiltrate the brain and cause neurodegeneration in histiocytic disorders.
- Author
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Wilk CM, Cathomas F, Török O, Le Berichel J, Park MD, Bigenwald C, Heaton GR, Hamon P, Troncoso L, Scull BP, Dangoor D, Silvin A, Fleischmann R, Belabed M, Lin H, Merad Taouli E, Boettcher S, Li L, Aubry A, Manz MG, Kofler JK, Yue Z, Lira SA, Ginhoux F, Crary JF, McClain KL, Picarsic JL, Russo SJ, Allen CE, and Merad M
- Subjects
- Humans, Brain metabolism, Myeloid Cells metabolism, Cell Differentiation, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins B-raf metabolism, Histiocytosis, Langerhans-Cell genetics, Histiocytosis, Langerhans-Cell pathology, Histiocytosis, Langerhans-Cell therapy
- Abstract
Neurodegenerative diseases (ND) are characterized by 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 mitogen-activated protein kinase (MAPK)-activating mutations that differentiate into senescent myeloid cells that drive lesion formation. Some individuals with LCH subsequently develop progressive and incurable neurodegeneration (LCH-ND). Here, we showed that LCH-ND was caused by myeloid cells that were clonal with peripheral LCH cells. Circulating BRAFV600E
+ myeloid cells caused the breakdown of the blood-brain barrier (BBB), enhancing migration into the brain parenchyma where they differentiated into senescent, inflammatory CD11a+ macrophages that accumulated in the brainstem and cerebellum. Blocking MAPK activity and senescence programs reduced peripheral inflammation, brain parenchymal infiltration, neuroinflammation, neuronal damage and improved neurological outcome in preclinical LCH-ND. MAPK activation and senescence programs in circulating myeloid cells represent targetable mechanisms of LCH-ND., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)- Published
- 2023
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