Novel research sheds light on the beneficial aspects of neuroinflammation and may spur directed therapies for white matter diseases

By Holly Kerr, Hotchkiss Brain Institute

Most of the nerves in our bodies are covered with a protective layer called myelin. We can think of myelin as functioning similarly to the insulation on electric wires: it facilitates the movement of messages from the brain through our body smoothly and efficiently, like the way electricity flows from a power source.

Health conditions that damage myelin, called demyelinating disorders, cause scar tissue to form in place of the myelin, obstructing brain signals from moving throughout our body, and preventing nerves from functioning at their best. Some commonly known demyelinating disorders include multiple sclerosis, amytrophic lateral sclerosis (ALS), Parkinson’s disease and stroke – conditions that can cause vision loss, deficiencies in muscle coordination and sensation, speech and language impediments, and incontinence.

Researchers at the University of Calgary’s Hotchkiss Brain Institute (HBI) at the Cumming School of Medicine, and Faculty of Veterinary Medicine, are working to understand the myelin repair process – known as remyelination – and how the immune system contributes to it.

Drs. Jason Plemel, PhD, now at University of Alberta (former supervisors Drs. V. Wee Yong and Peter Stys, HBI, Cumming School of Medicine) and Jo Anne Stratton, PhD, now at McGill University (former supervisor Dr. Jeff Biernaskie, HBI, Faculty of Veterinary Medicine and Department of Surgery at the Cumming School of Medicine) and members of their research team know that cells called microglia (residing in the brain and spinal cord) and others called macrophages (residing in blood and peripheral tissues) both play a role in remyelination. Until now, however, it’s been close to impossible to distinguish between them, as they appear almost identical at the molecular level.

Without the ability to distinguish between microglia and macrophages, researchers struggled to fully understand their functions and how each of them contributes to the remyelination process in the injured spinal cord.

In a recent study published in Science Advances, lead author Plemel and his colleagues took a novel approach and developed a genetic trick that identifies only microglia in the spinal cord and brain. By isolating the microglia, which are uniquely marked with a red fluorescent protein in the study, Plemel and Stratton were able to see the different ways microglia and macrophages contribute to remyelination. The results indicate that after a demyelinating injury, the number of microglia expands and appear to have a neuroprotective function, preventing the macrophages from entering the central nervous system and therefore limiting their peripheral inflammatory effects on the brain and/or spinal cord.

Additionally, when the team genetically eliminated the microglia following a damage to the spinal cord myelin, the macrophage numbers increased at the site of injury, making the injury much worse than it originally was.

Ultimately, these findings indicate that the microglia are beneficial players in remyelination, and may be an important cellular target that could be modulated to improve brain and spinal cord repair when myelinated nerves are damaged either by injury or disease.

The next challenge for researchers will be to develop drugs that either duplicate the benefits offered by the microglia, or prevent the macrophages from entering the injured central nervous system. Now that researchers understand the different roles of the microglia and macrophages, an opportunity may be on the horizon to develop treatments that will vastly improve remyelination and injury repair.

Additional study authors include Dr. Rajiv Midha, MD, and Dr. Peter Stys, MD, both with the Department of Clinical Neurosciences and the HBI at the Cumming School of Medicine.

This study was funded in part by Canadian Institutes for Health Research (CIHR), MS Society of Canada, Alberta Heritage Foundation for Medical Research, University of Alberta start-up funds for Dr. Jason Plemel and a CRIO Team grant from Alberta Innovates Health Solutions (AIHS). Dr. Jo Anne Stratton was supported by the Alberta Children’s Hospital Foundation as a postdoctoral fellow at the Alberta Children’s Hospital Research Institute (ACHRI). Dr. Jeff Biernaskie, also a member of ACHRI, is supported by the Calgary Firefighters Burn Treatment Society Chair in Skin Regeneration and Wound Healing. Drs. Peter Stys and V. Wee Yong are supported by Canada Research Chair (Tier 1) awards.

Led by the Hotchkiss Brain Institute, Brain and Mental Health is one of six strategic research themes guiding the university towards its Eyes High goals.