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Immune Cells May Heal Bleeding Brain After Strokes


Accounting for 10-15% of all strokes, intracerebral hemorrhages happen when blood vessels rupture and leak blood into the brain, often leading to death or long-term disability. Chronic high blood pressure is the leading risk factor for these  types of strokes. The initial phase of damage appears to be caused by the pressure of blood leaking into the brain. Over time, further damage may be caused by the accumulation of toxic levels of blood products, infiltrating immune cells, and swelling. Neutrophils are born in bone marrow and carry chemicals in hundreds of densely filled packets called granules, which look like dark spots under a microscope. Typically, when the body senses bacteria or an injury, neutrophils rush to the invasion site and release germ killing chemicals from the granules. This appears to happen minutes after a hemorrhagic stroke.


According to the NIH, decades of research suggest that neutrophils are some of the earliest immune cells to respond to a hemorrhage, and that they may both harm and heal the brain. In the present study, published in Nature Communication (20 September 2017), it was found that interleukin-27 (IL-27), a protein that controls the activity of immune cells, may shift the role of neutrophils from harming the brain to helping with recovery. Results showed that injections of IL-27 after a hemorrhage helped mice recover and that days after the strokes, the treated mice had better mobility, including walking, limb stretching and navigating holes in a floor. In contrast, injections of an antibody that blocked natural IL-27 activity slowed recovery. At autopsy, the brains of the mice treated with IL-27 also showed less damage. They had less swelling around the hemorrhages and lower levels of iron and the blood protein hemoglobin, both of which are toxic at high levels.


Based on the results of the study, the authors hypothesized that after a hemorrhagic stroke, the brain secretes high levels of IL-27, which leads to a second wave of neutrophils arriving with granules filled with higher amounts of healing molecules. IL-27 levels were elevated in the brain and blood of the mice an hour after hemorrhages, and stayed high for three days, peaking at 24 hours. Further experiments suggested that brain cells called microglia produced the IL-27 in response to the presence of red blood cells.


Once released, IL-27 molecules appeared to travel to the bones of the mice, infiltrated the marrow, and changed the role newborn neutrophils played in response to a stroke. When the authors extracted newborn neutrophils from the bones of mice and treated and them with IL-27, IL-27 raised the activity of genes associated with healing, especially lactoferrin, while reducing the activity of genes associated with killing cells. Conversely, treating mice with an IL-27 neutralizing antibody after a hemorrhage, lowered lactoferrin gene activity.


Finally, the authors showed the iron binding protein lactoferrin may protect the brain from intracerebral hemorrhagic strokes. Mice and rats injected with lactoferrin 30 minutes after hemorrhages recovered faster and had reduced brain damage as compared to animals given placebo treatment. In one set of experiments, even giving mice lactoferrin 24 hours after a stroke was also effective.



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