June 30, 2016
Researchers pin down molecule that permits the entry of harmful immune cells into the spinal cord in MS-like disease
One of the ways that researchers gain important insights into a complex disease like multiple sclerosis (MS) is by studying how different molecules interact in order to trigger and drive the disease. Certain molecules can play multiple, sometimes conflicting roles in the MS disease process. One such molecule is interleukin-1 (IL-1); while it can contributes to the development of MS-like symptoms in mice, IL-1 also appears necessary for remyelination, a regenerative process used to replace myelin damaged during an MS-like attack.
IL-1 encompasses a large family of genes. One of the best studied is IL-1b, a type of molecular messenger used by cells to communicate with one another; one cell releases IL-1b, which then seeks out and binds its receptor (called IL-1R1) on another cell’s surface. This binding instructs the cell to carry out any number of functions, such as to release inflammatory molecules or migrate a great distance away.
In an effort to better understand the role that IL-1b plays in MS, a research team from Université Laval conducted a study to investigate IL-1R1 signaling in mice with an MS-like disease. The team included MS Society-funded researchers Drs. Steve Lacroix and Alexandre Prat as well as endMS Transitional Career Development Award holder Dr. Jorge Alvarez. Their work, published in The Journal of Experimental Medicine, concentrates on the IL-1b/IL-1R1 system and its effect on the immune system during an MS-related attack.
Dr. Lacroix and his team first set out to determine if genetically removing either IL-1b or its receptor IL-1R1 could affect the development of an MS-like disorder in mice. They then conducted a series of experiments to identify the cells responsible for producing IL-1b as well as those carrying the IL-1R1 receptor. Throughout the study, the team focused their attention on the spinal cord, as it was the site in which IL-1b was found to spike during an MS-like attack.
The researchers then tested to see if cells carrying IL-1R1 released pro-inflammatory molecules in response to IL-1b, using both human and mouse cells grown in a dish as well as in mice with an MS-like disorder.
In a final set of experiments, the researchers transferred the IL-1b-producing cells into the spinal cords of mice that were unable to manufacture any IL-1b of their own. The team was then able to assess what role, if any, the IL-1b producingcells played in the development of MS-like symptoms in mice.
MS-like symptoms were both slower to develop and less intense in mice that lacked either IL-1b or its receptor IL-1R1.
Two types of immune cells, neutrophils and macrophages, were responsible for producing IL-1b in the spinal cord during an MS-like attack. The IL-1b molecule targeted and bound endothelial cells, a type of cell that lines the inside blood vessels found in the spinal cord. Once bound, endothelial cells released pro-inflammatory molecules known to recruit and activate inflammatory immune cells.
When injected into mice with an MS-like disorder, IL-1b-producing neutrophils and macrophages caused a massive inflammatory response at the injection site as well as increased symptom severity manifested as more frequent paralysis of the hindlimbs.
IL-1b appears to lie at the heart of an inflammatory loop; neutrophils and macrophages enter the spinal cord and release IL-1b, causing local endothelial cells that line the blood vessels to recruit and activate additional immune cells from the blood. During an MS-like attack in mice, the accumulation of immune cells due to IL-1b worsens symptoms and increases the likelihood of limb paralysis.
Endothelial cells are of particular interest since they help form the blood-spinal cord barrier, one of the spinal cord’s primary lines of defense against invasion. This tightly-knit layer of cells acts as a gatekeeper between the blood and spinal cord, restricting potentially damaging molecules and cells, such as activated neutrophils and macrophages, from entering the spinal cord. In MS, aggressive immune cells infiltrate and disrupt the barrier, causing widespread inflammation and damage to the spinal cord. Dr. Lacroix’s study suggests that IL-1b-producing neutrophils and macrophages manipulate the barrier to recruit even more pro-inflammatory cells, aggravating inflammation and compounding damage during an attack.
While the authors do not comment on IL-1b’s possible role in the remyelination process, their findings are part of a concerted effort to find targets that block inflammatory immune cells from crossing the blood-spinal cord barrier and attacking the central nervous system. The hope is that these targets can eventually be translated into a new pipeline of disease-fighting therapies for people living with MS.
Lévesque SA et al. (2016) Myeloid cell transmigration across the CNS vasculature triggers IL-1b-driven neuroinflammation during autoimmune encephalomyelitis in mice. Journal of Experimental Medicine. 213(6): 929-49.