Neuroscientists have discovered that the type of white blood cell that serves as a first responder to tissue damage can travel directly from the bone marrow cavities inside our skulls to the outer layer of the membrane surrounding our brains using never before seen microscopic channels. It was previously believed that most of the immune cells tasked with brain maintenance were produced by reservoirs of spongy marrow inside our arm and leg bones, and that they could only be delivered to the meninges by circulating through the bloodstream.
"These findings suggest that immune cells may instead be taking a shortcut to rapidly arrive at areas of inflammation," said Francesca Bosetti, program director at the NIH's National Institute of Neurological Disorders and Stroke (NINDS), which provided funding for the study, in a statement. "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."
In their revelatory paper, published in Nature Neuroscience, Dr Nahrendorf and his colleagues from Massachusetts General Hospital and Harvard Medical School document how the pathway was first revealed through a series of experiments with fluorescently tagged neutrophils in mice. After marking neutrophils made in the mice’s tibias and skull bones, the authors inflicted brain damage by inducing a stroke or creating brain inflammation. Subsequent advanced imaging scans showed that the neutrophils arriving on the scene were more likely to have come from the skull marrow than that of the tibia, and that the neutrophil supply within the skull bone was much more depleted than that of the tibia and other white blood cell sources.
Interestingly, the team then found that heart tissue injuries from induced heart attacks resulted in similar responses from skull and tibia neutrophils. Taken together, the evidence suggested that skull bone marrow reacts differently to signals from the injured brain than it does to distress from other parts of the body. Yet at this point, they still didn’t understand how the neutrophils got to the dura matter – the outermost layer of the meninges – so quickly.
Using confocal microscopy, Nahrendorf’s team was able to analyze the dense bone with high precision, noting with surprise that not only were there tiny vascular channels dotted throughout but that neutrophils in brain-injured mice were moving against the normal direction of blood flow to enter the dura matter.
An investigation of human skull bone specimens taken from surgical patients confirmed that these channels also exist in humans.
Naturally, it will take some time to unravel how the skull marrow response is regulated, but the data gathered thus far indicates that an inflammatory molecule called cell-derived factor-1 may be the trigger.
"While we've still got a lot to learn about these channels, I think their very special role as conduits for inflammatory cross-talk between the marrow and the central nervous system is quite different from any other vasculature," said lead researcher Dr Mathias Nahrendorf.
He adds that the next step will be to assess how these channels are involved in human brain conditions including strokes, hypertension, and dementia. "Another idea is that the channels could serve as a route of drug delivery, allowing transport to the meninges of drugs delivered into the skull marrow."