Scientists have discovered secret corridors that connect the bone marrow in the skull directly to the brain. According to a paper published August 27 in Nature Neuroscience, these tiny channels serve as an express route for marrow cells, including neutrophils, to cross into the cortex in response to injury. The researchers, led by Matthias Nahrendorf of Massachusetts General Hospital in Boston, challenge the prevailing view in the field that bone marrow-derived cells recruited to the brain hail primarily from the blood, which carries cells collectively released from all sources of bone marrow in the body.
- Neutrophils infiltrating the brain hail from the skull bone marrow more so than other bones in the body.
- They travel via small vascular channels connecting the skull marrow directly to the dura mater.
- People and mice have the channels.
“This is a novel access route to the brain for inflammatory cells and its discovery, while providing new insight into the pathobiology of post-ischemic inflammation, contributes to debunk the myth of the immune privilege of the brain,” wrote Costantino Iadecola of Weill Cornell Medical College in New York. “Furthermore, inasmuch as innate and adaptive immune cells participate in neurodegeneration, the findings also have implications for Alzheimer’s disease and related conditions,” he added.
As the sole supplier of short-lived myeloid cells in the body, the bone marrow pumps out multitudes of leukocytes, including neutrophils, in response to injury or insult. Researchers have spotted such myeloid cells infiltrating the brain in response to stroke, traumatic brain injury, or in the context of neurodegenerative disease, but exactly which marrow sources supply those cells is unclear (Offner et al., 2006; Courties et al., 2014; Aug 2015 news).
First author Fanny Herisson and colleagues investigated whether neutrophils recruited to the brain in response to injury came from marrow in the skull, or equally from other marrow sources. To test this, they injected different cell-permeant fluorescent dyes into the tibia and the skull. They then monitored the neutrophils that took up the dyes and flooded the brain in response to stroke or aseptic meningitis. About twice as many neutrophils came from the skull as from the tibia. In contrast, triggering a brief cardiac arrest summoned neutrophils to the heart that derived equally from both bones. The data suggested that brain injury specifically recruits bone marrow cells from the skull.
The researchers hypothesized that a direct vascular connection could exist. Indeed, confocal microscopy of mouse brain sections revealed a dense network of 21-micron-diameter vessels crisscrossing the inner surface of the skull and connecting to the brain’s dura mater. The outsides of the vessels were speckled with microcalcifications from nearby osteoblasts, and their insides were lined with endothelial cells. Neutrophils and monocytes were seen in the lumen of these channels. Using time-lapse microscopy of freshly harvested sections of mouse skulls immersed in a bath of media, the researchers detected blood flowing through the channels from the brain toward the skull. Strikingly, neutrophils in the channels crawled against the current, making their way from the skull toward the brain. This cross-current traffic increased after a stroke.
Against the Current. A neutrophil (green) travels from the skull toward the brain through a calcium-coated (white) microchannel lined with endothelial cells (red). [Courtesy of Herisson et al., Nature Neuroscience, 2018.]
To search for the channels in people, the researchers imaged skull sections taken from three patients to relieve pressure caused by swelling from traumatic brain injury or other trauma. They found a similar network of channels feeding into the associated dura, though at about fivefold larger in diameter than those in mice. They have yet to determine whether they function similarly.—Jessica Shugart
- Offner H, Subramanian S, Parker SM, Afentoulis ME, Vandenbark AA, Hurn PD. Experimental stroke induces massive, rapid activation of the peripheral immune system. J Cereb Blood Flow Metab. 2006 May;26(5):654-65. PubMed.
- Courties G, Moskowitz MA, Nahrendorf M. The innate immune system after ischemic injury: lessons to be learned from the heart and brain. JAMA Neurol. 2014 Feb;71(2):233-6. PubMed.
No Available Further Reading
- Herisson F, Frodermann V, Courties G, Rohde D, Sun Y, Vandoorne K, Wojtkiewicz GR, Masson GS, Vinegoni C, Kim J, Kim DE, Weissleder R, Swirski FK, Moskowitz MA, Nahrendorf M. Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration. Nat Neurosci. 2018 Aug 27; PubMed.