People living with multiple sclerosis know all too well that for them, the immune system is a double-edged sword. Although it acts as a sophisticated alarm and defense system that protects the body from infection by pathogens like certain bacteria and viruses, it can also turn on its own tissues and attack them. This process, called autoimmunity, is the hallmark of MS. This Janus-like quality of the immune system doesn’t just end there; individual types of immune cells can be harmful or beneficial, depending on the circumstances. In this post, I’ll be looking at microglia and trying to answer the question: are they friend or foe?
Microglia: what do they do?
Microglia belong to a type of immune cell called a macrophage that reside exclusively in the central nervous system (CNS), making up around 10% of the cells in the brain and spinal cord. Microglia are versatile cells and fulfill a variety of functions. Under normal circumstances, microglia serve a “housekeeping” role, pruning unwanted connections between nerve cells in the brain and scavenging for the occasional cellular debris. In this way, they act as scouts that patrol and monitor their local environment for pathogens or damaged tissue by “tasting” their surroundings with arm-like extensions. This constant surveillance pays off: in the event of an invading infection that crosses the blood-brain barrier into the CNS, microglia act as the first line of defense. They become activated and quickly mobilize to contain the infection and stop it from spreading and damaging sensitive nervous tissue.
One approach used by microglia to mount a defense is called phagocytosis, a process by which microglia engulf a particle (such as a virus or a piece of debris) and break it down. Another method, called cytotoxicity, releases certain toxic substances into the local environment that can destroy cells, although as we will learn later, cytotoxicity can cause potentially harmful collateral damage. In addition to their direct actions, microglia release signalling molecules called cytokines and chemokines that recruit heavy duty immune cells from the periphery, such as T cells and macrophages. After taking in antigens (a fragment of protein that can be recognized by a specific antigen receptor), microglia can present these antigens to T cells, causing them to become activated, increase in number and mount a concerted immune response.
Microglia come in different shapes and sizes, and they can be classified at two opposite extremes based on their appearance and function. “M1” cells are generally proinflammatory since they tend to release proinflammatory cytokines and chemokines and promote cytotoxicity. On the other hand, “M2” cells tend to be anti-inflammatory and neuroprotective, a concept that I will return to in a few paragraphs. Of course, this is an oversimplification and in reality, microglia sit along a spectrum between the M1 and M2 extremes but, for the purposes of this article, distinguishing between M1 and M2 will do just fine.
Microglia and MS
So what kind of role do microglia play in the MS brain? The answer is not quite so simple, and a great deal of research has been poured into helping us understand how microglia participate in the MS disease process at every step of the way.
It’s been known for a while that activated microglia cluster in the brain lesions of people living with MS, and that the M1 type of microglia tends to predominate at the early, actively inflammatory stage of the disease. Insights into the functions of these microglia have been gained from studying mice with an MS-like disease. Several studies have demonstrated that using genetic techniques or drugs to effectively shut off microglia in mice with an MS-like disease can significantly curb disease onset and alleviate clinical symptoms. The destructive properties of microglia are believed to come in several forms: indirectly, they release signaling molecules that promote the recruitment of destructive T cells and, through taking in antigens and presenting them on their surface, they activate these infiltrating T cells and trigger them to attack the myelin sheath surrounding nerve fibres. Microglia can also directly strip off myelin and destroy myelin-producing cells and nerve cells by releasing cytotoxic molecules, and blocking the actions of these cytotoxic molecules in animals with an MS-like disease has been shown to reduce disease severity.
On the other hand, emerging research is showing that microglia aren’t necessarily always the bad guys, and in fact can play an important role in promoting the repair of myelin, a process called remyelination. While M1 type microglia release proinflammatory cytokines, M2 microglia secrete anti-inflammatory cytokines that also serve to attract cells called oligodendrocyte precursor cells (OPCs) to sites of damage and trigger them to mature into myelin-producing cells called oligodendrocytes. When a group of researchers led by Dr. Glenn Matsushima (University of North Carolina) switched off one of these cytokines, called interleukin-1β, in mice with an MS-like disease, nerve fibres that had been stripped of myelin failed to remyelinate properly, demonstrating that M2 microglia can help to drive remyelination.
More recently, an MS Scientific Research Foundation-funded study conducted by Drs. Peter Stys and V. Wee Yong examined the role of microglia in stimulating efficient remyelination through the clearance of myelin debris left over from autoimmune attack. The team genetically inactivated microglia by switching off a specific receptor called CX3C receptor 1, and examined remyelination in mice after triggering an MS-like disease. What they found was that phagocytosis of myelin fragments from previous demyelination was severely obstructed, which led to disorganized repair of the damaged myelin. This finding added to the mounting pile of evidence that microglia are important players that help to guide myelin repair.
In addition to promoting remyelination, beneficial microglia can protect nerve cells from damage, a process called neuroprotection. A study published by MS Society funded Postdoctoral Fellow Dr. Zhihong Chen (Cleveland Clinic) demonstrated that certain activated microglia can protect nerve cells in the adult mouse brain by releasing survival-enhancing molecules and pruning away inhibitory connections that stop neurons from functioning properly. By chemically blocking the activity of these microglia, the neuroprotective benefits were lost. These findings are of particular importance for research into therapeutics for progressive MS, since underlying neurodegeneration is one of the primary culprits for the accumulation of disability that is a defining feature of progressive MS.
Microglia: A therapeutic target?
As the diverse roles of microglia in the MS disease process continue to be unearthed, researchers are looking at tapping into the protective and remyelinating properties of microglia while switching off their destructive ones. Progress in this area has been picking up the pace in recent years, with a number of targets associated with microglia being identified and flagged for potential therapies. One of these targets is galectin-1, which has been shown to attach to microglia and deactivate the proinflammatory M1 form. In the process, galectin-1 can promote neuroprotection and improve disease symptoms in mice with an MS-like disease, opening it up as a therapeutic avenue for MS.
Another target was identified just this month by MS Society-funded investigator Dr. Denis Gris (University of Sherbrooke). This protein, called Nlrp12, sits on the surface of microglia and helps to keep their inflammatory properties in check. When Nlrp12 is shut off in mice with an MS-like disease, activated microglia produce more pro-inflammatory and cytotoxic molecules and increase the severity of clinical symptoms, leading Dr. Gris to the conclusion that Nlrp12 plays a protective role that could potentially be harnessed as a therapeutic option.
Perhaps the closest we’ve approached to successfully targeting microglia is using minocycline, which belongs to a class of antibiotics that are commonly prescribed to treat acne. Minocycline is an inhibitor of microglia, and studies in which mice with an MS-like disease were treated with minocycline demonstrated a reduction in demyelination and an improvement in clinical symptoms. Based on promising findings in animal studies, the efficacy of minocycline in reducing the risk of conversion to MS in people who have experienced a first clinical demyelinating event was studied in a clinical trial led by Dr. Luanne Metz (University of Calgary). The results of this trial, which was funded by the MS Society and the MS Scientific Research Foundation, were recently presented at the ECTRIMS 2015 conference in Barcelona and showed very promising results.
At the same time, researchers are looking into exploiting the positive properties of microglia to help promote remyelination and neuroprotection in individuals who have already experienced demyelination, and MS Society-funded researchers are leading the charge. The study by Drs. Stys and Wee Yong that I described earlier examined a receptor that when switched off, prevented the ability of microglia to clear away myelin debris and promote efficient remyelination. Similarly, Dr. Zhihong Chen carefully documented the ability of certain microglia to prevent nerve cell damage from occurring in the first place, opening new doors for neuroprotective therapies.
Whether they’re friend or foe, microglia are here to stay, and the job of researchers in the years to come will be to keep microglia on our side and join the fight against MS.
Do you have any questions about microglia? Leave them below!
- Chen Z et al. Microglial displacement of inhibitory synapses provides neuroprotection in the adult brain. Nature Communications. 2014. 5:4486.
- Gharagozloo M et al. The nod-like receptor, Nlrp12, plays an anti-inflammatory role in experimental autoimmune encephalomyelitis. J Neuroinflamm. 2015. 12:198.
- Goldman T & Prinz M. Role of Microglia in CNS Autoimmunity. Clin Dev Immunol. 208093.
- Lampron A et al. Inefficient clearance of myelin debris by microglia impairs remyelinating processes. J Exp Med. 2015. 212(4):481-95.
- Mason JL et al. Interleukin-1beta promotes repair of the CNS. J Neurosci. 2001. 21(18):7046-52.
- Pasquini A et al. The neurotoxic effect of cuprizone on oligodendrocytes depends on the presence of pro-inflammatory cytokines secreted by microglia. Neurochemical Research. 2007. 32(2):279-92.
- Skripuletz E et al. Beneficial effects of minocycline on cuprizone induced cortical demyelination Neurochemical Research. 2010 35(9):1422-33.
- Strachan-Whaley M et al. Interactions between microglia and T cells in multiple sclerosis pathobiology. J Interferon Cytokine Res. 2014 34(8):615-22.