MS Society of Canada funded study reveals a new mechanism that prevents the death of brain cells in MS
Background: Mechanisms leading to brain damage in MS are not fully understood
One hallmark of multiple sclerosis (MS) is the loss of myelin, the protective covering on the nerve fibers, found in the brain and spinal cord, collectively called the central nervous system (CNS). The loss of myelin leads to the disruption of signals from the CNS to the body causing the various symptoms experienced by an individual diagnosed with MS. Damage of myelin is a central event in MS and leads to inflammation, but the triggers of inflammation are not entirely understood.
There is evidence to support that inflammatory signals in MS are triggered by a group of proteins called inflammasomes. The activation of these inflammasomes leads to a particular type of cell death called pyroptosis or “fiery death”.
Currently, cell death mechanisms in MS are broadly investigated. It is known that the two particular cell types that are susceptible to death in MS are oligodendrocytes and microglia. Oligodendrocytes are responsible for myelin production and are damaged in MS but the mechanism underlying their death remains unknown. Similarly, microglia are the primary immune cells in the CNS and their role is to remove debris and stimulate immune responses, however, the factors regulating their survival in MS are still being investigated.
To better understand the causes of inflammation and cell death in MS, neurologist and researcher from the University of Alberta, Dr. Chris Power, examined the mechanisms regulating inflammation and cell death in MS. This work, supported by the MS Society of Canada and University Hospital Foundation, was recently published in Proceedings of the National Academy of the United States of America (PNAS).
The Study: Investigating the role of cell death in MS using human tissue, animal models of MS, and lab-grown cells
Using post-mortem human tissue, animals with MS-like disease, and lab-grown cells, the goal of the research team was to: (1) identify the presence of inflammasome activators; (2) delineate the mechanism through which inflammasomes trigger damage in the brain; and (3) find a therapeutic target that could block this detrimental effect.
Results: A group of proteins contributing to inflammation, called inflammasomes, lead to the “fiery” death of two cells types involved in MS: microglia and oligodendrocytes
Using post-mortem human tissue, the research team was able to identify molecules (or factors) associated with inflammasomes in MS brains. Furthermore, the team discovered that inflammasome activators can induce fiery death (or pyroptosis), a type of cell death that is associated with inflammation, in microglia and oligodendrocytes. Taking it a step further to identify a potential therapeutic option, mice with an MS-like disease were treated with the inflammasome blocker called VX-765 which reduced CNS inflammation, and improved clinical outcomes in animal models of MS.
Overall, Dr. Power and his research team described a novel mechanism of cell death in MS and identified a potential therapeutic option (VX-765) for the treatment of MS. This drug is currently in clinical trials for epilepsy and is shown to be safe in humans. However, some questions remain unanswered concerning this drug in MS: (1) Does this drug also impact non-MS related inflammasome activation outside the CNS? and (2) Would this drug also block inflammasomes outside the brain and spinal cord that also contribute to MS disease progression?
In summary, inflammasome activation and fiery cell death are presented as new therapeutically targetable mechanisms driving inflammation and demyelination in MS, opening the door to a new class of treatment that can reduce brain cell damage.
McKenzie BA et al. (2018) Caspase-1 inhibition prevents glial inflammasome activation and pyroptosis in models of multiple sclerosis. Proc Natl Acad Sci U S A. 115:E6065-e6074.