Inflammation occurs as an immune response to instances of infection or injury within the body.
The immune response is subject to a complex process of coordination that involves a type of spongy tissue known as bone marrow.
Bone marrow can be found inside a number of bones, including the skull, the vertebrae of the vertebral column, and leg bones, such as the tibia.
This tissue produces both red blood cells and some types of immune cells, all of which are involved in inflammation, responding to injuries or infections.
Now, a study conducted by researchers from the Harvard Medical School in Boston, MA, and partly funded by the National Institutes of Health (NIH), has discovered how the brain and bone marrow coordinate to ensure a quick, targeted immune response.
The answer, the specialists explain in a paper featured in the journal Nature Neuroscience, lies in previously unknown channels that allow the two to communicate.
"We always thought that immune cells from our arms and legs traveled via blood to damaged brain tissue. These findings suggest that immune cells may instead be taking a shortcut to rapidly arrive at areas of inflammation," explains Francesca Bosetti, program director at the NIH's National Institute of Neurological Disorders and Stroke.
"Inflammation plays a critical role in many brain disorders and it is possible that the newly described channels may be important in a number of conditions. The discovery of these channels opens up many new avenues of research."
The injured brain recruits help from the skull
The researchers first conducted their study in a mouse model, and once they knew what to search for, they were also able to replicate their findings in humans.
Using advanced optical imaging techniques, they tracked the movements of neutrophils, a type of immune cell typically first to migrate to places in the body that have sustained an injury.
Specifically, the researchers could find out whether neutrophils that reached brain tissue damaged as the result of a stroke or meningitis were released from bone marrow found in the skull or from marrow found in the tibia.
Looking at brains of mice, the scientists saw that during a stroke, injured brain tissue receives neutrophils from the skull, rather than the tibia, in most cases.
During a heart attack, however, the researchers revealed that the heart is likely to receive a similar number of neutrophils from both skull and tibia marrow, seeing as the heart is situated farther from both of those bone structures.
Also, they noted that 6 hours after a stroke occurs, there are fewer neutrophils in the marrow of the skull than in that of the tibia.
What this suggests is that the injured brain tissue and the marrow found in the skull have a direct means of "communication," which allows for a quick and targeted immune response from the closest "respondent."
An 'unexpected' discovery
How does this all happen? The first clue about the mechanisms involved came from a bone marrow protein known as stromal cell-derived factor-1 (SDF-1), whose role is to regulate when immune cells are stored in the bone marrow and when they are released.
When SDF-1 levels drop, the bone marrow releases neutrophils, so they can attend to the injured tissue.
The team noted that SDF-1 levels decrease 6 hours after a stroke only in the marrow found in skull bones, which indicates that the bone marrow found in the skull is in direct communication with the brain, which "alerts" it of the damage, "recruiting" the closest source of help.
"We [then] started examining the skull very carefully, looking at it from all angles, trying to figure out how neutrophils are getting to the brain," explains study co-author Dr. Matthias Nahrendorf.
"Unexpectedly, we discovered tiny channels that connected the marrow directly with the outer lining of the brain," he adds.
Dr. Nahrendorf and his team identified such "tiny channels" of communications not just all over the skull, but also in the tibia.
Following these findings in mice, the researchers then searched for the same structures in humans and found them; the channels they observed in human skulls were five times larger than the ones seen in mice, they report.
Moreover, in mice as well as in humans, the channels appear both in the inner and outer layers of the skull.
In the future, the scientists are eager to see what other types of cells may move through these newly discovered channels and to uncover more information about how these tiny passages mediate the immune response.