MS Society of Canada-funded study uncovers a protein that keeps inflammatory cells in check
Microglia are specialized immune cells found only in the brain and spinal cord of the central nervous system (CNS). When activated, these cells help coordinate the inflammatory response in a healthy system; stimulating the recruitment of other immune cells as well as clearing leftover cellular debris. However, activated microglia are also involved in the autoimmune response that lies at the heart of MS; they are capable of releasing harmful neurotoxic and pro-inflammatory molecules, as well as mobilizing various inflammatory immune cells that damage the CNS.
Recently, a team of researchers, led by Dr. Denis Gris at the University of Sherbrooke in Quebec, has identified a protein that sits on the surface of microglial cells and regulates this inflammatory process. The protein, called Nlrp12, was hypothesized to ultimately be protective and suppress inflammation. Funded by the MS Society of Canada and Fonds de recherche du Québec—Santé, the study was published in the Journal of Neuroinflammation.
To get a clearer picture of Nlrp12’s role in the MS immune response, the research team experimentally removed the Nlrp12 gene from mice. An MS-like disorder was then induced in these genetically modified mice, allowing Dr. Gris and his team to study whether removal of Nlrp12 affected the animals’ clinical outcome (limb and tail paralysis), or the inflammatory response in the animals’ spinal cords (including the presence of pro-inflammatory molecules and activation of microglia).
To better understand the role of Nlrp12 in the context of microglia, the researchers also used cell culture techniques. Using this method, the team grew microglia taken directly from the genetically modified mice and tested whether activated microglia released more toxic and/or pro-inflammatory molecules when Nlrp12 was absent.
When Nlrp12 was genetically removed, mice with an MS-like disorder developed symptoms that appeared earlier and were more severe compared to mice with Nlrp12 intact. A possible cause was quickly found; their spinal cords had much higher levels of various pro-inflammatory molecules, as well as a greater number of activated pro-inflammatory microglia.
When taken and grown in culture, activated microglia lacking Nlrp12 produced more neurotoxic and pro-inflammatory molecules, which confirmed the authors’ findings in the live animal studies.
These findings suggest that, during an autoimmune attack like in MS, Nlrp12 is protective, acting as a barrier that keeps the microglia’s pro-inflammatory properties at bay. If the protein is missing, mice with an MS-like disorder will have a more active and inflammatory immune system, accompanied by an increase in the severity of clinical symptoms.
Identifying and studying these types of proteins (called “stop-gate” proteins) not only enriches our understanding of the MS inflammatory response, but also provides insight and direction as we move forward with the generation of protective therapeutics. This is important, as not all aspects of microglia activation are harmful. In a previous update, we described work from Dr. Peter Stys’ laboratory which showed that microglia helped to boost remyelination capacity (the body’s ability to repair damaged myelin following an MS attack) by clearing away cellular debris following an MS-like attack in mice. Ultimately, the work carried out by Dr. Gris, Dr. Stys and others is part of a concerted effort to guide future therapeutic strategies targeting microglia that must balance supporting myelin repair with suppressing harmful inflammation.
Gharagozloo M et al. (2015). The nod-like receptor, Nlrp12, plays an anti-inflammatory role in experimental autoimmune encephalomyelitis. Journal of Neuroinflammation. 12:198.