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Role of clonal inflammatory microglia in histiocytosis-associated neurodegeneration
Rocio Vicario1, Stamatina Fragkogianni1, Maria Pokrovskii1
1Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Abstract:
Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders associated with mitogen-activated protein (MAP)-kinase-activating mutations and an increased risk of neurodegeneration. We found microglial mutant clones in LCH and ECD patients, whether or not they presented with clinical symptoms of neurodegeneration, associated with microgliosis, astrocytosis, and neuronal loss, predominantly in the rhombencephalon gray nuclei. Neurological symptoms were associated with PU.1+ clone size (p = 0.0003) in patients with the longest evolution of the disease, indicating a phase of subclinical incipient neurodegeneration. Genetic barcoding analysis suggests that clones may originate from definitive or yolk sac hematopoiesis, depending on the patients. In a mouse model, disease topography was attributable to a local clonal proliferative advantage, and microglia depletion by a CSF1R-inhibitor limited neuronal loss and improved survival. These studies characterize a neurodegenerative disease associated with clonal proliferation of inflammatory microglia. The long preclinical stage represents a therapeutic window before irreversible neuronal depletion.
Insights
Clonal myeloid disorders like Langerhans cell histiocytosis and Erdheim-Chester disease involve mutant microglia, leading to neurodegeneration. Targeting these inflammatory microglia offers a therapeutic window before irreversible neuronal loss.
Area of Science:
- Neuroscience
- Oncology
- Genetics
Background:
- Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders.
- These conditions are linked to MAP-kinase-activating mutations and neurodegeneration risk.
Purpose of the Study:
- Investigate the role of microglial mutant clones in LCH and ECD.
- Determine the association between these clones and neurodegeneration.
- Explore therapeutic strategies targeting microglia.
Main Methods:
- Genetic barcoding analysis of patient samples.
- Histopathological examination of brain tissue.
- Mouse models of LCH/ECD with microglia depletion (CSF1R-inhibitor).
Main Results:
- Microglial mutant clones found in LCH/ECD patients, with or without neurodegeneration symptoms.
- Associated microgliosis, astrocytosis, and neuronal loss, mainly in rhombencephalon.
- Neurological symptoms correlated with clone size in long-standing disease, indicating preclinical neurodegeneration.
- Mouse model showed local clonal proliferation drives disease and microglia depletion improves survival.
Conclusions:
- LCH and ECD involve clonal proliferation of inflammatory microglia, causing neurodegeneration.
- A significant preclinical stage exists, offering a therapeutic window.
- Targeting microglia presents a promising therapeutic strategy.
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