Written by Bethany Hoernfeldt, Science Writer
New discoveries made by researchers shed light on the origin of the brain’s immune system. Contrary to previous beliefs, CNS macrophages do not fully mature until after birth. This breakthrough provides valuable insights into normal CNS development, and may open avenues for a more profound understanding of neurological diseases.
The researchers found that the central nervous system (CSN) macrophages involved in the protection and reinforcement of the blood-brain barrier (BBB) mature much later than previously thought. Using genetically modified mouse cell lines and human brain tissue, they investigated the transcriptional programmes and distribution of the cells of interest.The study, recently published in Nature, provides valuable insights into the normal development of these cells, and may offer further clues into the causes and treatment of neurological diseases.
The brain is protected by a highly selective gatekeeper of microvascular endothelial cells and blood vessels that control which substances and cells can enter the CNS. The BBB is designed to be impermeable to large molecules, immune cells, and pathogens. Macrophages such as parenchymal glia and CNS-associated macrophages (CAMs) are vital components of the innate immune system of the CNS. Not only are they among the first cells to spring to action during infections and trauma, but they also surround the blood vessels of the CNS and fortify the BBB.
Previously, these immune cells were thought to mature during embryonic development. However, the researchers found that, even though the cells journey toward the blood vessels prior to birth, they may not mature until weeks into life.
“The late timing of the maturation of the phagocytes, also called macrophages, was very surprising to us, since the precursor cells are already present in the brain long before,” said Prof. Dr Marco Prinz, corresponding author of the study. “This process … could partly explain why the brain is so vulnerable at the beginning of life.”
Progeny with different fates
To start, the team investigated the transcriptional profiles and distribution of these cells in mouse cell lines. When they are mature, microglia and CAMs bear distinct gene expression profiles and occupy defined niches. In mature CAMs, for example, MRC1, LYVE1, CD163, SIGLEC1, and MS4A7 are highly expressed.
Meningeal and perivascular macrophages – two types of CAMs – are both derived from prenatal erythromyeloid progenitors but occupy different areas of the CNS at different time points. To further investigate the importance of this in the establishment of the BBB, the researchers labelled the cells, and determined their positions using transmission electron microscopy. Meningeal macrophages were identified in the leptomeninges, or the thin layers of tissue that surround the brain and spinal cord. Perivascular macrophages, on the other hand, migrated to perivascular Virchow-Robin spaces in the brain.
The researchers then extended their work to human foetal and postnatal brain tissue and made an important discovery. Unlike their cousins, the perivascular macrophages were barely detectable until gestational week 25, but then their numbers increased notably close to and after the time of birth.
The data offers new insights into the origin of the brain’s immune system.
“This gives us a much deeper understanding of the timing and molecular mechanisms in the development of cells. This knowledge can now be used to explore new and more specific therapeutic approaches for brain diseases,” said Dr Lukas Amann, co-author of the paper.
In fact, according to Prinz, macrophages are also involved in the development of diseases such as cancer, Alzheimer’s disease, and multiple sclerosis. Thankfully, this study provides valuable insight into normal CAM biology and CNS development, which in turn may be used to explore novel targeted treatments for neurological diseases.
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