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 recently discovered a series of tiny channels in mice and human skulls, and in mice at least, these little pathways represent an unexpected source of brain immunity.
Previously, scientists assumed that the immune system connects with the brain by slipping through a kind of neurological customs gate – a barrier separating blood channels from important neural tissue.
Now it seems there's no need to go the long way around after all. Immune cells inside the very bone that surrounds the brain appear to have a more direct path.
Last year, researchers found a whole host of immune cells hidden in the bone marrow of the mouse cranium. When confronted with a virus or tumor in the brain, these cells traveled through the skull channels and into 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 flow to the brain, researchers found that cerebrospinal fluid can also seep through to the skull.
Experts think it works sort of like an immune pit stop.
Channel in the human skull. (Herisson et al., Nature Neuroscience, 2022)
As the clear liquid that soaks the mammalian brain flows through cracks in the skull, it is closely monitored for threats by cells in the bone marrow.
If a pathogen is detected, the bone marrow responds by producing immune cells to fight off the infection.
Fluorescent tracers, injected into the cerebrospinal fluid of mice, clearly show cerebrospinal fluid traveling through sub-millimeter channels in the skull cap to the bone marrow.
When researchers injected mice brains with the bacteria that causes meningitis, which triggers inflammation of the brain's membrane or meninges, the infection began circulating within the cerebrospinal fluid.
Both the fluid and the bacteria then invaded the skull via these small channels and stimulated an immune system response.
Bacteria (green) entering the skull channel in the mouse brain. (Herisson et al., Nature Neuroscience, 2022)
An hour after injecting the bacteria into the mouse brain, 99 percent of stem cells in the skull bone marrow were labeled with a respective antibody.
"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," says Matthias Nahrendorf, who works at Massachusetts General Hospital and Harvard University.
"Cells in the skull's bone marrow are surveilling the cerebrospinal fluid that exits the brain through the skull channels we discovered earlier."
In 2018, Nahrendorf and his colleagues realized that the bone marrow in the mammalian skull is directly connected to the meninges via tiny little vascular channels in the bone.
In the years since then, it's become clear that the skull is an overlooked source of immune surveillance. Before that, it was assumed the health of the mammalian brain was monitored by distant immune sites elsewhere in the body.
But the new research suggests these other sites are not as involved, at least not initially. An hour after researchers injected mice with an intracerebral pathogen, peripheral bone marrow in a mouse leg bone did not show antibody-labeled cells. Skull bone marrow, however, did.
This suggests the immune system embedded in the skull takes care of neurological infections first.
"Generally, the skull marrow warrants closer scrutiny due to its proximity to and crosstalk with the meninges and the [central nervous system]," the authors write in their new paper.
"Constant sampling of [cerebrospinal fluid] outflow suggests that the skull marrow state may reflect brain health and that the skull marrow has a prominent role in regulating [central nervous system] inflammation."
A closer look with immunostaining revealed that bone marrow in the mouse skull had a slightly different composition of immune cells than bone marrow from the mouse tibia.
In the skull, neutrophils, which are the immune system's first line of defense, and monocytes, which kill invaders or alert other blood cells to action, were significantly enriched after injecting the mouse brain with bacteria. These immune cells were also clustered near sinuses where cerebrospinal fluid flows and bone marrow is rich.
The results suggest that cerebrospinal fluid has direct access to the skull bone marrow. What's more, immune cells can exit the skull bone marrow in response to cues from the cerebrospinal fluid.
Most of the time, this pathway is helpful. By consistently checking cerebrospinal fluid for invaders and responding accordingly, the skull's immune system keeps the mammalian brain healthy.
So what happens if this immune system is kicked into overdrive?
"This likely has huge implications for conditions like dementia and Alzheimer's disease because these diseases have an inflammatory component," says Nahrendorf.
While the findings have not yet been replicated among humans, it's likely that our brains show a similar system that bypasses the blood-brain barrier. Using micro CT scans, the authors have already found similar tiny channels connecting the human skull to the brain's meninges, each about 1.5 millimeters in diameter.
Whether white blood cells and cerebrospinal fluid also flow through these channels in our own species is unclear.
Human neurological conditions like multiple sclerosis, myasthenia gravis, and Guillain-Barré syndrome are all marked by an overactive immune response, but how this response is jumpstarted is still being figured out.
"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," adds Nahrendorf.
"Understanding what fuels neuro-inflammation is the first step to successfully modulating it."
The study was published in Nature Neuroscience.