(ORDO NEWS) — A shortcut between the skull and the brain could be a possible way for the human immune system to bypass the blood-brain barrier.
Researchers have recently discovered a number of tiny channels in the skulls of mice and humans, and, at least in mice, these small pathways represent an unexpected source of brain immunity.
Previously, scientists thought the immune system connected to the brain by slipping through a kind of neurological customs gate, a barrier that separates blood channels from important nerve tissue.
Now it seems there is no need to go the long way. Immune cells within the bone itself, which surrounds the brain, seem to have a more direct route.
Last year, researchers discovered a range of immune cells hidden in the bone marrow of mouse skulls. When faced with a virus or tumor in the brain, these cells travel through the channels of the skull and enter the cerebrospinal fluid.
Now it seems that this secret path is actually a two-way street.
Not only can immune cells in the skull cap leak into the brain, researchers have found that cerebrospinal fluid can leak into the skull as well.
Experts think it works like an immune pit stop.
When the clear fluid that soaks in the brains of mammals flows through cracks in the skull, bone marrow cells closely monitor it for threats.
If a pathogen is detected, the bone marrow responds by producing immune cells to fight the infection.
Fluorescent tracers injected into the cerebrospinal fluid of mice clearly show how the cerebrospinal fluid travels through submillimeter channels in the skull cap to the bone marrow.
When the researchers injected bacteria into the brains of mice that cause meningitis, which leads to inflammation of the lining of the brain or meninges, the infection began to circulate in the cerebrospinal fluid.
Both fluid and bacteria then entered the skull through these small channels and stimulated the immune system to respond.
One hour after injecting the bacteria into the mouse brain, 99 percent of the stem cells in the skull bone marrow were labeled with the appropriate antibody.
“We now know that the brain can signal this immune center – in other words, call for help if something goes wrong, such as during an infection or inflammation,” says Matthias Nahrendorf, who works at Massachusetts General Hospital and Harvard University.
“Cells in the bone marrow of the skull monitor the cerebrospinal fluid that exits the brain through the canals of the skull that we discovered earlier.”
In 2018, Nahrendorf and colleagues realized that the bone marrow in the mammalian skull is directly connected to meninges through tiny vascular channels in the bone.
In the years since, it has become clear that the skull is an overlooked source of immune surveillance. Previously, it was thought that remote immune sites in other parts of the body monitored the health of the mammalian brain.
But the new study suggests that these other sites are not as heavily involved in the process, at least not initially. An hour after the researchers injected the mice with an intracerebral pathogen, the peripheral bone marrow in the leg bones of the mouse did not detect antibody-labeled cells. But the bone marrow of the skull showed.
This suggests that the immune system built into the skull primarily takes care of neurological infections.
“Overall, the cranial marrow deserves closer attention because of its proximity to and cross-talk with the meninges and the [central nervous system],” the authors write in their new paper.
“Continuous sampling of [cerebrospinal fluid] outflow suggests that bone marrow status may reflect brain health and that bone marrow plays an important role in regulating [central nervous system] inflammation.”
A closer look using immunostaining showed that the bone marrow in the mouse skull had a slightly different composition of immune cells than the bone marrow from the mouse tibia.
In the skull, after injecting the bacteria into the mouse brain, there was a significant increase in the number of neutrophils, which are the immune system’s first line of defense, and monocytes, which kill invaders or alert other blood cells to action. These immune cells also clustered near the sinuses, where the cerebrospinal fluid flows and where the bone marrow resides.
The results obtained suggest that the cerebrospinal fluid has direct access to the bone marrow of the skull. Moreover, immune cells can be released from the bone marrow of the skull in response to signals from the cerebrospinal fluid.
In most cases, this path is useful. By constantly checking the cerebrospinal fluid for invaders and responding accordingly, the immune system of the skull keeps the mammalian brain healthy.
What happens if this immune system starts to work in an enhanced mode?
“This could make a huge difference in diseases like dementia and Alzheimer’s because these diseases have an inflammatory component,” says Nahrendorf.
Although the results of the study have not yet been replicated in humans, it is likely that a similar system operates in our brain that bypasses the blood-brain barrier. Using microtomography, the authors have already found similar tiny canals connecting the human skull to brain meninges, each about 1.5 millimeters in diameter.
Whether white blood cells and cerebrospinal fluid pass through these channels in our species is not yet clear.
Human neurological diseases such as multiple sclerosis, myasthenia gravis, and Guillain-Barré syndrome are characterized by an overactive immune response, but how this response is triggered remains to be seen.
“Our work could also be useful for studying situations where the immune response is harmful, such as when bone marrow-derived immune cells damage the brain and surrounding nerves,” adds Nahrendorf.
“Understanding what fuels neuroinflammation is the first step to successfully modulating it.”
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