Background
The degradation of the myelin sheath that surrounds nerves in the central nervous system (CNS), an event referred to as demyelination, is a hallmark of multiple sclerosis. Remyelination is the body’s natural mechanism of repairing myelin, although this process is compromised during MS, particularly in the progressive form of the disease where the imbalance favouring demyelination over remyelination contributes to chronic degeneration of nerve cells and accumulation of disability.
Efficient and functional remyelination can be hampered by the build-up of myelin by-products at an injury site during demyelination. Specialized immune cells are recruited to the site of demyelination and clear myelin debris by engulfing and degrading particles in a process called phagocytosis. Two immune cell types that participate in this process are microglia and macrophages. Although microglia and macrophages have traditionally been viewed as harmful players in MS due to their proinflammatory effects in the autoimmune response, their potentially beneficial role in stimulating efficient remyelination through the clearance of myelin debris has been largely overlooked.
New data has emerged from a study funded by the Multiple Sclerosis Scientific Research Foundation that connects myelin debris clearance by microglia with remyelination. The study is a collaborative, multi-centre effort led by Dr. Peter Stys and colleagues, and was published this month in the Journal of Experimental Medicine.
The Study
This study used a variety of genetic, biochemical, and molecular techniques in mice with an MS-like disease to study the roles played by microglia and macrophages during demyelination and remyelination. The researchers were able to target and switch off receptors (a protein on the surface of a cell that binds to chemical signals and changes the behaviour of the cell) specific to each type of immune cell in order to control their activity and entry into sites of demyelination.
Mice were genetically modified to allow the researchers to switch off, or knock out, one of two receptors: CC receptor 2 (CCR2), which permits macrophage infiltration into the CNS, and CX3C receptor 1 (CX3CR1), which is involved in the activity and migration of microglia. Mice were divided into testing groups based on their specific genetic modification: CCR2 knockouts, CX3CR1 knockouts, and their wild type (non-knockout) littermates.
The researchers induced an MS-like disease in mice using the molecule cuprizone, which causes widespread demyelination in the CNS. Cuprizone was then discontinued after several weeks, and the researchers monitored subsequent remyelination as well as the activity and recruitment of microglia and macrophages in the different testing groups. They also examined different measures of phagocytosis to study the effects of these knockouts on the clearance of myelin debris.
Results
Firstly, the researchers blocked the recruitment of macrophages to demyelinating sites in CCR2 knockout mice to study the role of macrophages in myelin repair. They found that the absence of macrophages had no effect on either demyelination or remyelination, suggesting that these cells are not involved in the repair of myelin.
When the researchers looked at remyelination in the CX3CR1 knockout mice who had impaired microglial activity, they found that phagocytosis of myelin debris was severely impeded, leading to abnormal remyelination. Although the rate of remyelination was unaffected in these mice, the researchers noticed that the repaired myelin was disorganized and had a number of defects, suggesting that blocking the clearance of myelin debris by microglia following demyelination results in inefficient remyelination.
Comment
This study identifies a new therapeutic target that could potentially benefit people with progressive forms of MS by shifting the balance away from demyelination toward efficient remyelination at sites of chronic injury in the CNS. The abnormal pattern of remyelination in mice with impaired microglial activity underscores the critical role of CX3CR1 in promoting the clearance of degenerated myelin debris and permitting remyelination to proceed unobstructed.
The authors propose that boosting the process of phagocytosis by microglia can eventually be part of an overall treatment strategy that combines stimulating myelin repair with suppressing harmful inflammation. One unanswered question is whether promoting microglia-induced remyelination can lead to clear, demonstrable benefits that halt the progression of disability, a goal that is hampered by a shortage of reliable, validated animal models for progressive MS. Nonetheless, the findings of this study will go a long way toward enriching our understanding of myelin repair mechanisms and developing new therapeutic options for people living with progressive MS.
Source
Lampron A et al. (2015). Inefficient clearance of myelin debris by microglia impairs remyelinating process. J Exp Med. [Epub ahead of print]