Immune cells in skull’s bone marrow appear to have unique profile

Immune cells in the skull’s bone marrow show distinct molecular profiles from those of other bones throughout the body, and they may provide critical clues into how immune cells drive inflammation in neurological disorders like multiple sclerosis (MS) a study reports.

“These findings carry profound implications, suggesting a far more complex connection between the skull and the brain than previously believed,” Ilgin Kolabas, a PhD student at Helmholtz Munich in Germany and the study’s first author, said in a university news story.

The study, “Distinct molecular profiles of skull bone marrow in health and neurological disorders,” was published in Cell.

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This work “opens up a myriad of possibilities for diagnosing and treating brain diseases and has the potential to revolutionize our understanding of neurological diseases” from Alzheimer’s to stroke, said Ali Ertürk, a neuroscientist at Helmholtz Munich and the study’s senior author.

MS is driven by inflammation in the brain and spinal cord that damages the myelin sheath, a fatty covering around nerve fibers. Inflammation in the brain, or neuroinflammation, also is thought to play a role in driving brain damage in many other neurological disorders, from Alzheimer’s to stroke.

Neuroinflammation is driven by the activity of immune cells. Almost all immune cells begin their lives in the bone marrow — spaces inside of bones where stem cells can divide and mature to form immune cells and other types of blood cells.

As the closest bone to the brain, the skull and its bone marrow may play a role in neuroinflammation. However, little is known about the activity of the skull bone marrow, and whether this differs from the marrows of other bones in the body.

A team of scientists in Germany conducted a battery of experiments to learn more.

“It remains unclear whether the expression profiles [which genes are turned on or off] of skull bone marrow cells are distinct from those of other bones and whether different types of bone marrows react differently to brain injury,” the scientists wrote.

Initial imaging tests were conducted to track the movement of immune cells in skull bone marrow in a mouse model of stroke. The scientists found that, after a stroke causes brain damage, immune cells — particularly myeloid cells, a class of immune cells involved in the early steps of inflammation — move from the skull’s bone marrow into damaged parts of the brain.

Researchers next looked at the makeup of cells in the skull marrow, and compared it to the makeup of other bones in the mice’s bodies. They also compared differences in gene activity and protein levels among immune cells in the marrow of different bone types.

Neutrophils in skull marrow also found in membranes surrounding brain

Immune cells in the skull’s marrow had a unique molecular profile compared with cells in other bones, particularly in a type of myeloid immune cell called neutrophils, the scientists reported. The unique profile of skull marrow neutrophils also was seen among neutrophils in the membranes that surround the brain, implying that these cells can move into the brain to trigger inflammation.

“Our study shows that there is a clear difference between the marrow cells suggesting localized functions for different bones,” the researchers wrote. They added that “the response of the [skull bone marrow] to neurological pathologies is different from other bones, indicating that the skull may be useful for monitoring and potentially controlling inflammation in various brain pathologies in the future.”

Researchers next sought to determine the relevance of these findings for people, using analyses of human bone samples collected after death. As in the mice, they found a distinct molecular profile in cells of the skull marrow compared to other bones.

Positron emission tomography (PET) imaging also was used to assess the inflammatory activity of skull immune cells in people with MS, Alzheimer’s, or stroke.

Using a radioactive tracer designed to bind TSPO, a protein that’s increased during inflammation, they found signs of greater inflammatory activity among immune cells in the skull — though the specific pattern of activity differed in each of the conditions.

The researchers highlighted a need for further studies to investigate these differences in greater detail and explore their potential clinical applications.

“Our detailed demonstration of skull inflammation in diverse diseases in humans suggests that it can be used for diagnosing or monitoring diseases in the future, but detailed clinical studies are needed to explore its clinical utility,” the scientists concluded.