Yale neurologists identify consistent neuroinflammatory response in ICH patients

February 22, 2021

Understanding how the immune system responds to acute brain hemorrhage could open doors to identifying treatments for this devastating disease. However, up until now, there has been limited information on inflammation in the brain from human patients, especially during the first days after a hemorrhagic stroke.

This led a team of researchers to partner with a large clinical trial of minimally-invasive surgery to tackle defining the human neuroinflammatory response in living patients.

"Our goal was to find out, for the first time, how certain key cells of the immune system are activated when they enter the brain after a hemorrhage and how this may shift over the first week. This is a critical time for our patients," said Lauren Sansing, MD, Academic Chief of Stroke and Vascular Neurology and Associate Professor of Neurology and Immunobiology at Yale.

The study, published in Science Immunology, was led by an interdisciplinary team of researchers including Sansing and Michael Askenase, PhD, Associate Research Scientist (both of Yale), and MIT scientists Alex Shalek, PhD, J. Christopher Love, PhD, and Brittany Goods, PhD. Using RNA-sequencing, they found that CD14+ macrophages and neutrophils change rapidly in the brain over the first few days after the hemorrhage. They were also able to find signatures in the macrophages that were consistent in patients with good recovery.

According to the American Heart Association, intracerebral hemorrhage (ICH) makes up approximately 13% of all stroke cases. It occurs when a blood vessel bursts and releases blood into the brain, damaging the surrounding brain tissue. The mortality rate is up to 40%, most survivors are left with some disability, and there is no cure.

ICH generates an acute local immune response within and around the hematoma. Researchers have predicted that inhibiting this inflammation may improve patient outcomes, but so far haven't identified cellular and molecular targets that have been effective therapies in patients.

The study's research team partnered with the MISTIE III surgical trial, which implemented a minimally invasive surgery wherein tissue plasminogen activator (tPA) was administered via a small catheter to liquify the clot and allow drainage of blood from the brain over several days. The blood clots were shipped daily from hospitals around the nation to the Sansing Lab.

According to Dr. Askenase, "We used the detailed patient outcome measures collected by MISTIE III to identify key molecular circuits within CD14 monocytes/macrophages that correlated with good neurological outcomes, thereby uncovering potential mechanisms by which these cells may help contribute to patient recovery. In particular, we found that these cells preferentially use glycolytic metabolism to generate a key anti-inflammatory lipid known as prostaglandin E2 that, if it activates the right receptor, may have broad pro-recovery effects not only on neighboring immune cells, but also on brain-resident neurons and glia."

This could allow physicians to target the brain's immune response to ICH and unlock new treatment options for an otherwise deadly form of stroke, although further research is needed to study these pathways.

A study of this breadth demanded collaboration and coordination.

"This project could only be done with great team work across many institutions," said Dr. Sansing.

Dan Hanley, MD and the MISTIE III trial leadership, the coordination with the trial substudies through MTI:M3, the trial investigators and clinical coordinators nationwide who collected the samples and all the scientific collaborators were key to the study success. The investigators thank the patients and families who took part in the study.

"I'm proud to be a part of one of the leading ICH research teams in the country. The ability to learn deeply from surgical samples opens the door for exciting new avenues in ICH research," said Charles Matouk, MD, Chief of Neurovascular Surgery at Yale and the MISTIE III co-site PI and collaborator on the research.

The study serves as a model for future studies to leverage a brain hemorrhage clinical trial to gain significant insight into the fundamental mechanisms of the disease and provide a more targeted approach to treating ICH.
-end-


Yale University

Related Immune System Articles from Brightsurf:

How the immune system remembers viruses
For a person to acquire immunity to a disease, T cells must develop into memory cells after contact with the pathogen.

How does the immune system develop in the first days of life?
Researchers highlight the anti-inflammatory response taking place after birth and designed to shield the newborn from infection.

Memory training for the immune system
The immune system will memorize the pathogen after an infection and can therefore react promptly after reinfection with the same pathogen.

Immune system may have another job -- combatting depression
An inflammatory autoimmune response within the central nervous system similar to one linked to neurodegenerative diseases such as multiple sclerosis (MS) has also been found in the spinal fluid of healthy people, according to a new Yale-led study comparing immune system cells in the spinal fluid of MS patients and healthy subjects.

COVID-19: Immune system derails
Contrary to what has been generally assumed so far, a severe course of COVID-19 does not solely result in a strong immune reaction - rather, the immune response is caught in a continuous loop of activation and inhibition.

Immune cell steroids help tumours suppress the immune system, offering new drug targets
Tumours found to evade the immune system by telling immune cells to produce immunosuppressive steroids.

Immune system -- Knocked off balance
Instead of protecting us, the immune system can sometimes go awry, as in the case of autoimmune diseases and allergies.

Too much salt weakens the immune system
A high-salt diet is not only bad for one's blood pressure, but also for the immune system.

Parkinson's and the immune system
Mutations in the Parkin gene are a common cause of hereditary forms of Parkinson's disease.

How an immune system regulator shifts the balance of immune cells
Researchers have provided new insight on the role of cyclic AMP (cAMP) in regulating the immune response.

Read More: Immune System News and Immune System Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.