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Transformation of donor-derived bone marrow precursors into host microglia during autoimmune CNS inflammation and
A Flügel1, M Bradl, G W Kreutzberg
1Department of Neuroimmunology, Max-Planck-Institute of Neurobiology, Martinsried, Germany.
Abstract:
Macrophages in the brain can have a triple source. They may originate from recently blood-derived precursors, from the largely resident perivascular cell population (perivascular macrophages and related cells), and from intrinsic parenchymal as well as perivascular microglia. Although continuous exchange of part of the perivascular cell population with bone marrow-derived precursors is now accepted, the turnover of adult parenchymal microglia has remained enigmatic. Using bone-marrow chimeras carrying an unexpressed marker gene and carbon labeling of peripheral monocyte/macrophages in a combined model of facial nerve axotomy and transfer experimental autoimmune encephalitis, we demonstrate for the first time that there is an easy to induce exchange between parenchymal central nervous system (CNS) microglia and the macrophage precursor cell pool of the bone marrow. Furthermore, very low level infiltration of the CNS parenchyma by recently bone marrow-derived microglia could be observed after simple peripheral nerve axotomy that is followed by neuronal regeneration. Thus, microglial cells can be considered wanderers between the peripheral immune system and the CNS where they may act as a "Trojan horse" in infections. The fact that recently bone marrow-derived parenchymal microglia fully integrate into a regenerating brain nucleus' architecture encourages entirely new approaches for delivering genes into the adult CNS.
Insights
Brain macrophages, or microglia, can be replenished from bone marrow precursors. This study shows microglia can easily exchange with the bone marrow, offering new gene therapy approaches for the central nervous system (CNS).
Area of Science:
- Neuroimmunology
- Cell Biology
- Regenerative Medicine
Background:
- Brain macrophages, known as microglia, have diverse origins, including blood precursors and resident cells.
- The turnover and origin of adult parenchymal microglia have been poorly understood.
- While perivascular cell exchange with bone marrow is accepted, microglial turnover remained enigmatic.
Purpose of the Study:
- To investigate the origin and turnover of adult parenchymal microglia in the central nervous system (CNS).
- To determine if microglia can exchange with bone marrow-derived precursor cells.
- To explore the implications of microglial plasticity for CNS gene delivery.
Main Methods:
- Utilized bone-marrow chimeras with an unexpressed marker gene.
- Employed carbon labeling of peripheral monocyte/macrophages.
- Combined models of facial nerve axotomy and experimental autoimmune encephalitis.
Main Results:
- Demonstrated an easily inducible exchange between parenchymal CNS microglia and the bone marrow macrophage precursor pool.
- Observed low-level infiltration of CNS parenchyma by bone marrow-derived microglia after peripheral nerve axotomy and regeneration.
- Showed that newly bone marrow-derived parenchymal microglia integrate into regenerating brain architecture.
Conclusions:
- Microglia are dynamic cells capable of exchange with the peripheral immune system via the bone marrow.
- Microglia can act as a "Trojan horse" for CNS infections.
- The integration of bone marrow-derived microglia into the CNS architecture opens new avenues for adult CNS gene therapy.
