Grant: Project Grant

Over four million individuals are afflicted by different types of spinal cord injury (SCI). One of the consequences of SCI is the loss of neural tissue at the site of injury. This results in an inflammatory response characterized by the entry of immune cells that are essential for the clearance of cellular debris. It has been assumed that during this process the inflammatory response may also contribute to secondary bystander damage in the spinal cord, causing the death of neighbouring neurons and myelin-producing cells called oligodendrocytes. As a consequence of this, both lesion volume and demyelination increase with time. Because of the inability of the human spinal cord to repair itself, damages sustained after injury often lead to permanent functional deficits for which no cure is currently available. Among the factors that mediate neuroinflammation are molecules normally found within cells that get released upon cell lysis. These intracellular host molecules, called danger signals or alarmins, include the inflammatory protein interleukin (IL)-1 alpha and nucleotides. IL-1 alpha and nucleotides are normally sequestrated inside cells, where they participate in gene expression regulation. However, when released after cell damage and death, they become powerful activators of neuroinflammation. We recently discovered that in addition to its role in inflammation, IL-1 alpha can act on oligodendrocytes to reduce their expression of genes coding for cell survival. Our results also revealed that nucleotides, as well as possibly other alarmins, stimulate microglia to form a rim between infiltrating immune cells and reactive astrocytes, a response that we called the 'microglial scar' and which we believe plays a key role in regulating axon regeneration and plasticity. The main goal of this research proposal is to identify the cellular and molecular mechanisms involved in these responses and to utilize this knowledge to promote spinal cord repair after injury.