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Updated: May 10, 2025
Analysis of Microglia and Monocyte-derived Macrophages from the Central Nervous System by Flow Cytometry
Published on: June 22, 2017
Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice
Jung-Seok Kim1, Sébastien Trzebanski1, Sun-Hye Shin1
1Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
Abstract:
Microglia are parenchymal brain macrophages that are established during embryogenesis and form a self-containing cellular compartment that resists seeding with cells derived from adult definitive hematopoiesis. We report that monocyte-derived macrophages (MoMΦs) accumulate in the brain of aging mice with distinct topologies, including the nigrostriatum and medulla but not the frontal cortex. Parenchymal MoMΦs adopt bona fide microglia morphology and expression profiles. Due to their hematopoietic stem cell (HSC) derivation, monocyte-derived microglia (MoMg) are unlike yolk-sac-derived cells, targets of clonal hematopoiesis (CH). Indeed, using a chimeric transfer model, we show that the hematopoietic expression of DNMT3AR882H, a prominent human CH variant, renders MoMg pathogenic and promotes motor deficits resembling atypical Parkinsonian disorders. Collectively, we establish that MoMg progressively seed the brain of healthy aging mice, accumulate in selected areas, and, when carrying a somatic mutation associated with CH, can cause brain pathology.
Insights
Monocyte-derived macrophages infiltrate aging mouse brains, adopting microglia characteristics. When carrying a clonal hematopoiesis mutation, these cells cause brain pathology and motor deficits.
Area of Science:
- Neuroimmunology
- Hematopoiesis
- Brain Aging
Background:
- Microglia, the brain's resident macrophages, originate during embryogenesis and typically resist adult hematopoietic cell infiltration.
- Aging processes may alter brain immune cell dynamics, potentially allowing peripheral immune cell entry.
Purpose of the Study:
- To investigate the accumulation and characteristics of monocyte-derived macrophages (MoMΦs) in the aging brain.
- To determine if these cells, when carrying specific mutations, contribute to brain pathology.
Main Methods:
- Analysis of aging mouse brains to identify and characterize infiltrating monocyte-derived macrophages (MoMΦs).
- Chimeric transfer models to assess the pathogenicity of MoMΦs with specific hematopoietic mutations (DNMT3AR882H).
Main Results:
- MoMΦs accumulate in specific brain regions (nigrostriatum, medulla) of aging mice, adopting microglia morphology and expression profiles.
- MoMΦs carrying the DNMT3AR882H mutation, associated with clonal hematopoiesis (CH), become pathogenic.
- Hematopoietic expression of DNMT3AR882H in MoMΦs leads to motor deficits resembling atypical Parkinsonian disorders.
Conclusions:
- Monocyte-derived microglia (MoMg) progressively seed the aging brain and accumulate in distinct areas.
- MoMg carrying somatic mutations linked to CH can induce brain pathology and neurological deficits.
