Tiny channels discovered inside the human skull could be vital for the brain

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 series of tiny channels in the skulls of mice and humans, and in mice at least, these small channels represent an unexpected source of cerebral immunity.

Previously, scientists assumed that the immune system connects to the brain by slipping through some kind of neurological gate – a barrier separating blood channels from important neural tissue.

Now it seems there is no need to go far after all. Immune cells within the very bone that surrounds the brain seem to have a more direct path.

Last year, researchers found a whole host of hidden immune cells in the bone marrow of the mouse skull. When faced with a virus or tumor in the brain, these cells have traveled through the ducts of the skull and into the cerebrospinal fluid.

Now it seems that this secret path is actually a two-way street.

Not only can immune cells from the skull cap leak to the brain, but researchers have found that cerebrospinal fluid can also leak to the skull.

Experts think it works a bit like an immune pit stop.

Canal in the human skull. (Hérisson et al., Nature Neuroscience, 2022)

As the clear fluid that permeates the mammalian brain drains through cracks in the skull, it is closely monitored for threats from bone marrow cells.

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 that the cerebrospinal fluid travels through sub-millimeter channels from the skull cap to the bone marrow.

When researchers injected the brain of mice with the bacteria responsible for meningitis, which triggers inflammation of the membrane or meninges of the brain, the infection began to circulate in the cerebrospinal fluid.

Fluid and bacteria then invaded the skull through these small channels and stimulated an immune system response.

FRwwnMZUYAA2jGY Bacteria (green) entering the cranial canal in the mouse brain. (Hérisson et al., Nature Neuroscience, 2022)

One hour after injecting the bacteria into the mouse’s brain, 99% of stem cells in the bone marrow of the skull were labeled with a respective antibody.

“We now know that the brain can signal to this immunity center – in other words, call for help when something goes wrong, such as during infection and inflammation,” said Matthias Nahrendorf, who works at Massachusetts General Hospital and Harvard University.

“Bone marrow cells in the skull monitor cerebrospinal fluid exiting the brain through the cranial canals we discovered earlier.”

In 2018, Nahrendorf and his colleagues executed that the bone marrow in the skull of mammals is directly connected to the meninges via tiny little vascular channels in the bone.

In the years since, it has become clear that the skull is an overlooked source of immune surveillance. Prior to this, it was assumed that mammalian brain health was monitored by remote immune sites elsewhere in the body.

But the new research suggests that these other sites aren’t as involved, at least not initially. An hour after researchers injected mice with an intracerebral pathogen, peripheral bone marrow in a mouse leg bone showed no antibody-labeled cells. The bone marrow of the skull, however, did.

This suggests that the immune system embedded in the skull takes care of neurological infections first.

“Generally, the bone marrow merits further investigation due to its proximity and crosstalk to the meninges and the [central nervous system],” writers write in their new journal.

“A constant sampling of [cerebrospinal fluid] flow suggests that the state of the cranial medulla may reflect brain health and that the cranial medulla plays an important role in regulating [central nervous system] inflammation.”

Further examination with immunostaining revealed that mouse skull bone marrow had a slightly different composition of immune cells than mouse tibial bone marrow.

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 bacteria were injected into the brain of the mouse. These immune cells were also clustered near the sinuses where cerebrospinal fluid flows and bone marrow is rich.

The results suggest that cerebrospinal fluid has direct access to the bone marrow of the skull. Additionally, immune cells can exit from the bone marrow of the skull in response to signals from the cerebrospinal fluid.

Most of the time, this path is useful. By constantly checking the cerebrospinal fluid for invaders and reacting accordingly, the immune system in the skull keeps the mammalian brain healthy.

So what happens if that immune system is overworked?

“It probably has huge implications for conditions like dementia and Alzheimer’s because these diseases have an inflammatory component,” said Nahrendorf.

Although the results have not yet been replicated in humans, it is likely that our brains exhibit 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 meninges of the brain, each about 1.5 millimeters in diameter.

It is unknown whether white blood cells and cerebrospinal fluid also flow through these channels in our own species.

Human neurological conditions such as multiple sclerosis, myasthenia gravis, and Guillain-Barré syndrome are all marked by an overactive immune response, but how this response is triggered remains to be determined.

“Our work may also be useful for studying situations where the immune response is harmful, such as when immune cells derived from the bone marrow of the skull damage the brain and surrounding nerves,” adds Nahrendorf.

“Understanding what fuels neuroinflammation is the first step to successfully modulating it.”

The study was published in Natural neuroscience.

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