In multiple sclerosis (MS), the immune system mistakenly attacks the nervous system, leading to damage in the brain and spinal cord.
Normally, the immune system protects the body from infections, but in people with MS, it becomes overactive. This abnormal response is triggered by a combination of genetic and environmental factors. As a result, immune cells migrate into the brain and spinal cord, causing inflammation and injury to nerve tissue. This damage disrupts communication between nerve cells and leads to a variety of neurological symptoms, such as muscle weakness, balance problems, coordination difficulties, numbness, fatigue, and vision disturbances. These symptoms can appear in episodes (known as relapses) or progressively worsen over time.
A key group of immune cells involved in MS are the phagocytes. These cells play a central role in the immune response and are abundant in active MS brain lesions.
Phagocytes include different subtypes, such as macrophages and microglia. Macrophages originate from blood monocytes and enter the central nervous system (CNS) during MS lesion formation. Microglia, on the other hand, are resident immune cells that are already present in the brain. In MS, both macrophages and microglia become activated and contribute to nerve damage. They break down myelin, the fatty sheath that surrounds nerve fibers. Myelin is crucial for fast and efficient nerve signal transmission. When myelin is damaged, nerve communication is impaired, leading to the neurological problems seen in MS.
The brain has a natural ability to repair damaged myelin, a process called remyelination, which can restore nerve function. Because of this, researchers consider promoting remyelination an important treatment strategy for MS. For remyelination to take place, the brain must first establish an environment within the lesion that supports repair. While multiple cell types and processes are involved, phagocytes play a central role through two key steps. In a healthy immune response, this shift helps resolve inflammation and supports the generation of new myelin-producing cells. However, in MS, this transition often fails, and phagocytes remain in a chronic inflammatory state. This prolonged activation leads to the formation of slowly expanding brain lesions that lack remyelination. The presence of these lesions is strongly linked to disease progression.
The reasons why phagocytes in MS lesions fail to switch to their repair-promoting state are not yet fully understood, but several factors contribute to the problem. One major factor is the persistent activation of the immune system due to the autoimmune nature of MS. Additionally, phagocytes become overwhelmed by the large amount of myelin debris they must clear. The excessive accumulation of myelin-derived lipids disrupts their function and drives them into a harmful inflammatory state. Other factors, such as genetic predisposition, aging, gender, diet, and infections, may further contribute to the failure of lesion repair in MS.
Since unresolved inflammation plays a central role in MS, researchers are exploring therapies that promote its resolution to stimulate remyelination. Current treatments aim to suppress the infiltration and activity of phagocytes in the brain. For example, drugs such as Natalizumab and Fingolimod block molecules needed for immune cells to enter the CNS, while BTK inhibitors, and Dimethyl fumarate help reduce their inflammatory activity. Experimental approaches are also being developed to target phagocytes more specifically in the CNS. These strategies include enhancing myelin debris clearance and improving lipid processing, reprogramming cell metabolism, increasing the production of inflammation resolving lipid mediators, and reducing oxidative stress. While many of these strategies have shown promise in preclinical models, further research is needed to confirm their effectiveness in clinical trials.
Because MS presents differently in each patient, developing personalized treatments is essential. The complexity of the disease means that a combination of approaches targeting different aspects of MS pathology will likely be necessary. Despite the challenges, advances in research offer hope for future therapies that may slow disease progression and even promote recovery.
Prof. Jérôme Hendriks, Professor in Neuroimmunology, University of Hasselt