Immune cell-related proteins may speed healing after stroke

Brain nerve cells (green) and astrocytes (red), a type of support cell, in a rat cell culture after exposure to a mixture from red blood cells. The researchers used this as a model for the damage caused to the brain by intracerebral hemorrhagic stroke.Aronowski lab, University of Texas Health Science Center, Houston

Intracerebral hemorrhages are a form of stroke caused by ruptured blood vessels. The leaked blood causes swelling and increased pressure in the skull, which damage cells and tissues in the brain. Over time, additional damage may be caused by the buildup of toxic levels of blood products and infiltrating immune cells. Symptoms of a hemorrhagic stroke can include sudden weakness; paralysis or numbness of the face, arms, or legs; trouble speaking or understanding speech; and trouble seeing.

Decades of research suggest that neutrophils are some of the earliest immune cells to respond to a hemorrhage, and that they may have both harmful and healing effects in the brain. A team led by Dr. Jaroslaw Aronowski at the University of Texas Health Science Center at Houston set out to find out what role neutrophils may play in healing after hemorrhagic stroke. The study was funded by NIH’s National Institute of Neurological Disorders and Stroke (NINDS). Results appeared on September 19, 2017, in Nature Communications.

The team first measured interleukin-27 (IL-27), a protein that controls the activity of various immune cells, in the brain and blood of mice after a brain hemorrhage. They detected elevated IL-27 levels within an hour after hemorrhage. Levels peaked at 24 hours and remained high for 3 days. Further experiments suggested that brain cells called microglia produced IL-27 in response to the presence of red blood cells.

The team found that, once released, the IL-27 molecules appeared to travel to the bones of the mice and infiltrate the marrow, where neutrophils are born. When the researchers extracted neutrophils from the bones and treated them with IL-27, the chemical raised the activity of genes associated with healing. IL-27 may thus shift the role of neutrophils from harming to helping with recovery.

The researchers injected IL-27 into mice after a hemorrhage. Days after the stroke, the treated mice were better than untreated mice at walking, limb stretching, and navigating holes in a floor. The brains of the mice treated with IL-27 also showed less damage. They had less swelling around the hemorrhages and lower levels of two compounds that are toxic at high levels, iron and the blood protein hemoglobin. In contrast, injections of a compound that blocked natural IL-27 activity slowed recovery.

One notable gene for which IL-27 raised the level of activity in neutrophils was the gene for lactoferrin, a protein that neutralizes toxic iron. The team tested lactoferrin’s effect on stroke recovery. They injected mice and rats with lactoferrin 30 minutes after a brain hemorrhage. The treated animals recovered faster and had less brain damage than animals given placebos. Giving mice lactoferrin 24 hours after a stroke was also effective.

“Intracerebral hemorrhage is a damaging and often fatal form of stroke for which there are no effective medicines,” Aronowski says. “Our results are a hopeful first step towards developing a treatment for this devastating form of stroke.”