While immune system cells’ purpose is to defend and protect the body, ironically the brain’s “call to arms” may cause more harm than good when it instructs immune cells to enter into the brain. The persistence of these cells can cause chronic inflammation and damage the brain.

In their new study, described in the journal Science Signaling April 13, Johns Hopkins researchers say there is evidence that vesicles or small (about the size of a virus), fat–like molecules and protein–filled sacks released from a type of immune cell in the brain called astrocytes travel through the bloodstream to the liver. The liver then instructs white blood cells to go to the site of injury in the brain.

“Identifying this pathway has helped us pinpoint ways to impede this process and reduce brain damage brought on by the body’s own excessive immune response,” says Norman Haughey, PhD, professor of neurology at the Johns Hopkins University School of Medicine.

The team focused on an enzyme called neutral sphingomyelinase, known as nSMase2, which they knew from a separate project was turned on by an immune system chemical messenger, a cytokine interleukin 1–beta (IL–1b) that promotes inflammation. Sphingomyelinases like nSMase2 play a normal role in the cell’s metabolism by breaking down fatty molecules into smaller components that cells use for every day functions.

To see if possibly nSMase2 was also involved in alerting the immune system during brain injury, the researchers mimicked brain injury in mice by injecting cytokine IL–1b into the striatum, a structure found in the deep center of the brain. As a comparison group, they injected saline in the same brain area of other mice. They also injected the mouse brains with both the cytokine IL–1b and a drug called altenusin that blocks the nSMase enzyme from working.

Twenty–four hours after the injection, the researchers saw large numbers of immune system white blood cells in tissue samples of the rodent brains near the site of injury of those mice injected with the cytokine IL–1b, but not in the brain tissue of the control group of mice. In addition, they no longer saw the same large influx of white blood cells into the brain when they used the drug that inhibited nSMase, with the number of white blood cells in the brain dropping by about 90 percent. This finding told the researchers of nSMase2’s involvement but still didn’t tell them about the signal sent from the brain to activate the body’s immune response. According to Haughey, after many failed experiments to determine the brain’s messenger, he visited his colleague and collaborator Daniel Anthony at Oxford University, who introduced him to the concept of “exosomes” — miniature vesicles released from cells.

To test that exosomes were the source of this brain to body communication, Haughey’s research team isolated exosomes from the blood of mice four hours after injecting the cytokine IL–1b into brain and then injected the exosomes into the tail veins of different mice that had the cytokine and the nSMase–blocking drug altenusin already in their brains.

The researchers found that white blood cells in healthy mice who received exosomes from the blood of the mice with brain damage traveled to the site of brain injury, which the researchers say demonstrates that exosomes released from brain in response to damage alert the immune system to send the immune cell sentinels to the brain.

When they stripped the vesicles of protein and their genetic cargo and injected them back into mice, the blood cells no longer went to the site of brain injury.

Finally, the researchers analyzed the protein and genetic material contents of the exosomes in an effort to identify the molecules inside that alerted the immune system to brain damage. They found 10 unique proteins and 23 microRNAs at increased levels in the vesicles.