Press release

Tuesday, January 19, 2021

NIH study shows that a specific set of immune cells can harm and also help the brain after injury.

Researchers at the National Institutes of Health have discovered Jekyll and Hyde immune cells in the brain that ultimately help with brain repair, but soon after injury they can lead to fatal swelling, suggesting that the timing may be. be critical when administering treatment. These dual-purpose cells, called myelomonocytic cells, which are carried to the brain by blood, are just one type of brain immune cell that NIH researchers have tracked, observing brain repair after injury in real time. The study, published in Nature Neuroscience, was supported by the National Institute of Neurological Disorders and Stroke (NINDS) intramural research program at NIH.

“Repairing the brain after injury is a highly orchestrated and coordinated process, and giving treatment at the wrong time could end up doing more harm than good,” said Dorian McGavern, Ph.D., NINDS scientist and lead author of the study.

Cerebrovascular damage or damage to the blood vessels in the brain can occur as a result of several conditions, including traumatic brain injury or stroke. Dr. McGavern, along with NINDS scientist Larry Latour, MD, and colleagues observed that a subset of stroke patients developed bleeding and swelling in the brain after the clot was surgically removed. of blood vessel responsible for stroke. The swelling, also known as edema, leads to poor results and can even be fatal as the brain structures are compressed and damaged further.

To understand how vascular injury can lead to swelling and to identify potential treatment strategies, Dr. McGavern and his team developed an animal model of cerebrovascular injury and used advanced microscopic imaging to observe how the brain responds to damage over time. real.

Immediately after the injury, immune cells in the brain known as microglia mobilize quickly to prevent blood vessels from leaking. These immune system “first responders” stretch out and wrap their arms around broken blood vessels. Dr. McGavern’s group found that removing microglia causes bleeding and irreparable damage to the brain.

A few hours later, the damaged brain is invaded by peripheral monocytes and circulating neutrophils (or myelomonocytic cells). When myelomonocytic cells pass from the blood to the brain, they each open a small hole in the vascular system, causing a mist of fluid to enter the brain. When thousands of these cells rush into the brain simultaneously, a large amount of fluid enters at the same time and causes swelling.

“The myelomonocytic cells at this stage of repair have good intentions and want to help, but they enter the brain with too much enthusiasm. This can lead to devastating tissue damage and swelling, especially if it occurs around the brainstem, which controls vital functions such as breathing, ”said Dr. McGavern.

After this initial surge, the monocytic subset of immune cells enter the brain at a slower, less damaging rate and go to work to repair the vessels. Monocytes work with repair-associated microglia to rebuild the damaged vascular network, which is reconnected within 10 days of injury. Monocytes are necessary for this important repair process.

In the next set of experiments, Dr. McGavern and his colleagues tried to reduce secondary swelling and tissue damage by using a combination of therapeutic antibodies that block myelomonocytic cells from entering the brain. The antibodies blocked two different adhesion molecules that myelomonocytic cells use to attach to inflamed blood vessels. These were effective in reducing swelling in the brain and improving results when given within six hours of injury.

Interestingly, therapeutic antibodies did not work if they were given after six hours or if they were given for too long. In fact, treating mice for a series of days with these antibodies inhibited proper repair of damaged blood vessels, resulting in neuronal death and brain scarring.

“Timing is essential in trying to prevent fatal edema. You want to prevent swelling and acute brain damage, but you don’t want to block the monocytes from their beneficial repair work, ”said Dr. McGavern.

Plans are currently underway for clinical trials to see if giving treatments at specific times will reduce edema and brain damage in a subset of stroke patients. Future research studies will examine other aspects of the cerebrovascular repair process, in the hopes of identifying other therapeutic interventions to promote restorative immune functions.

This study was funded by the intramural research program NINDS.

NINDS is the largest national funder of brain and nervous system research. The mission of NINDS is to research fundamental knowledge about the brain and nervous system and to use this knowledge to reduce the burden of neurological disease.

About the National Institutes of Health (NIH):The NIH, the national agency for medical research, comprises 27 institutes and centers and is part of the US Department of Health and Human Services. The NIH is the principal federal agency that conducts and supports basic, clinical, and translational medical research, and studies the causes, treatments, and cures for common and rare diseases. For more information about the NIH and its programs, visit www.nih.gov.

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The references

Mastorakos P. et al. Temporal distinct myeloid cell responses mediate damage and repair after cerebrovascular injury. Natural neuroscience. January 18, 2021.

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