Bagged in three layers of meninges and selectively fenced off by the blood brain barrier, our central nervous system (CNS) interacts within strict limits with our immune system. Protective cerebrospinal fluid (CSF) that flows between the meninges and interfaces with the glymphatic system for waste clearance enables outward signaling beyond the blood–brain barrier. Until now, the known routes of CSF outflow were through villi in the arachnoid layer of the meninges, along spinal and cranial nerves and through lymphatics in the dura mater layer of the meninges to lymph nodes in the neck.

In an article published in the journal Nature Neuroscience on May 2, 2022 “Cerebrospinal fluid can exit into the skull bone marrow and instruct cranial hematopoiesis in mice with bacterial meningitis“, scientists at Massachusetts General Hospital (MGH) and Harvard Medical School (HMS) have discovered a new outflow route for CSF through the bone marrow of the skull.

“Cerebrospinal fluid carries signals related to brain pathologies. One could say it “washes” the neurons. To date, it was known that cerebrospinal fluid drains along nerves and into meningeal lymphatics. Here we show it drains into the skull bone marrow—a completely new exit path. This is relevant because the skull bone marrow hosts blood stem cells that produce white blood cells which can then migrate to the CNS,” said Matthias Nahrendorf, MD, PhD, an investigator in MGH’s center for systems biology, a professor of radiology at HMS, and a senior author of the current study.

Upon injecting fluorescent tracers into the cisterna magna in mice, one of three principal openings between the arachnoid and pia mater layers of the meninges surrounding the brain, the researchers found the tracers creep along blood vessels of the dura mater layer of the meninges and squeeze through numerous skull channels into the bone marrow of the brain box. The team used two-photon intravital microscopy and an ex vivo imaging pipeline to visualize CSF distribution after fluorescent tracer injection.

In mice with meningitis, the authors also show bacteria take over this path into the skull’s marrow, increasing emergency blood cell production in the cranium before hematopoiesis can be triggered in remote shin bones. Immune cells produced in the spongy tissue of the skull’s bone marrow can screen the CSF for signs of infection and other threats to the brain.

“As skull channels also directly provide leukocytes to meninges, the privileged sampling of brain-derived danger signals in CSF by regional marrow may have broad implications for inflammatory neurological disorders,” the authors noted.

Nahrendorf’s team had published in an earlier study that immune cells that infiltrate the brain upon infection or injury come from bone marrow in the skull, and not as previously believed, from bone marrow throughout the body. Nahrendorf’s team discovered that these immune cells pass through hundreds of tiny, previously unknown channels connecting the skull’s bone marrow to the outer meninges.

“We’re trying to better understand neuroinflammation, a source of considerable clinical burden (i.e. dementia), by following leukocytes upstream, and understanding the signals that trigger their increased supply,” said Nahrendorf.

The current study, led by Nahrendorf, Charles Lin, PhD, leader of the Advanced Microscopy Group at the Center for Systems Biology at MGH, and Michael Moskowitz, MD, a physician investigator at MGH who was awarded the 2021 Lundbeck Brain Prize, demonstrated that in addition to allowing immune cells to flow into the meninges from the skull, the skull channels also allow CSF to flow out of the brain and into the skull’s bone marrow.

“Now we know that the brain can signal to this hub of immunity—in other words, cry for help in case things go wrong, such as during infection and inflammation. Cells in the skull’s bone marrow are surveilling the cerebrospinal fluid that exits the brain through the skull channels we discovered earlier,” said Nahrendorf. “This likely has huge implications for conditions like dementia and Alzheimer’s disease because these diseases have an inflammatory component.”

First author of the study, Fadi Pulous, PhD, and the team also found that bacteria causing meningitis travel through the channels and enter the skull’s bone marrow, causing the production of more immune cells to combat the infection.

“Our work may also be helpful for studying situations when the immune response is harmful, such as when skull bone marrow–derived immune cells damage the brain and surrounding nerves. Understanding what fuels neuro-inflammation is the first step to successfully modulating it,” said Nahrendorf.

Among questions that the current study leaves unanswered are the fate of CSF after it enters the bone via the skull channels, whether migration of bacteria along blood vessels is restricted by size and whether bacteria move through skull channels by themselves or within white blood cells. Nevertheless, the insights from the study warrants a closer study of the skull marrow due to its proximity and crosstalk with the CNS, particularly since the study suggests that the state of the skull marrow may reflect brain health or inflammation of the CNS.

Nahrendorf intends to investigate the consequences of the new outbound CSF flow in diseases such as dementia and identify pathways that could be therapeutically modulated.

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