In multiple sclerosis, inflammation can successfully be prevented, while promoting repair is still a major challenge. Microglial cells, the resident phagocytes of the central nervous system (CNS), are hematopoietic-derived myeloid cells and express the triggering receptor expressed on myeloid cells 2 (TREM2), an innate immune receptor. Myeloid cells are an accessible source for ex vivo gene therapy. We investigated whether myeloid precursor cells genetically modified to express TREM2 affect the disease course of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis.
Methods and Findings
EAE was induced in mice by immunization with a myelin autoantigen. Intravenous application of TREM2-transduced bone marrow–derived myeloid precursor cells at the EAE peak led to an amelioration of clinical symptoms, reduction in axonal damage, and prevention of further demyelination. TREM2-transduced myeloid cells applied intravenously migrated into the inflammatory spinal cord lesions of EAE-diseased mice, showed increased lysosomal and phagocytic activity, cleared degenerated myelin, and created an anti-inflammatory cytokine milieu within the CNS.
Intravenously applied bone marrow–derived and TREM2-tranduced myeloid precursor cells limit tissue destruction and facilitate repair within the murine CNS by clearance of cellular debris during EAE. TREM2 is a new attractive target for promotion of repair and resolution of inflammation in multiple sclerosis and other neuroinflammatory diseases.
Myeloid precursors genetically modified to express TREM2 supported recovery in animals with experimental autoimmune encephalomyelitis by phagocytosis and removal of apoptotic cellular debris.
Multiple sclerosis (MS) is a progressive disease of the central nervous system (CNS; the brain and spinal cord) in which communications within the brain are disrupted. In healthy individuals, the brain controls the body by sending electrical messages along nerve fibers. Like electrical wires, these fibers have to be insulated to allow the efficient transfer of electrical impulses. This insulation is provided by myelin, a fatty tissue that surrounds the nerve fibers. In patients with MS, patchy myelin loss, inflammation, and scarring (sclerosis) disrupt nerve transmissions, causing weakness or paralysis of the limbs, balance and coordination problems, and numerous other symptoms. The damage to the myelin (which increases over time) is caused by the patient's immune system, but what triggers this abnormal behavior is unclear. There is no cure for MS, but drugs that modulate the immune system (for example, interferons and steroids) can slow its progression.
Why Was This Study Done?
Any treatment for MS needs to limit tissue destruction by the immune system and to promote the repair of the damaged myelin and nerve fibers. Although researchers have identified some agents that promote nerve repair, it is difficult to get them into the CNS, which is protected by an impermeable barrier. However, some cell types can migrate into the CNS so it might be possible to adapt them as delivery vehicles for therapeutic agents. In this study, the researchers investigated whether bone marrow–derived myeloid precursor cells (a source of several immune system cell types) might be useful for the treatment of MS, both as delivery vehicles and as a source of cells that can resolve inflammation and clear cellular debris from sites of myelin destruction; this clearance has to occur before nerves and myelin can be repaired. Myeloid precursor cells, the researchers reasoned, might satisfy both these requirements because they naturally migrate into the CNS where some turn into microglia, immune system cells that engulf and digest cellular debris.
What Did the Researchers Do and Find?
The researchers isolated myeloid precursor cells from mouse bone marrow and induced the expression of triggering receptor expressed on myeloid cells-2 (TREM2, a protein made by microglia) in them using a viral vector. They injected these TREM2-expressing cells into the veins of mice with experimental autoimmune encephalomyelitis (EAE, an animal model of MS) and examined their migration into the spinal cord, their effect on EAE symptoms, and their effect on cell debris clearance and inflammatory responses in spinal cord lesions. Neither TREM2-expressing nor control myeloid precursor cells migrated into the spinal cord when injected into healthy mice or into animals just beginning to show the symptoms of EAE. However, both cell types migrated into the spinal cord when injected into animals when EAE symptoms were at their peak. The injection of TREM2-expressing myeloid precursor cells (but not control myeloid precursor cells) at this time reduced EAE symptoms and nerve damage, and halted myelin loss. It also increased the clearance of cell debris and myelin fragments and created an anti-inflammatory environment in the spinal cord lesions.
What Do These Findings Mean?
These findings indicate that the intravenous injection of bone marrow–derived myeloid precursor cells engineered to express TREM2 can reduce clinical symptoms and induce recovery in mice with EAE. Whether the TREM2-expressing myeloid precursor cells act locally in the CNS or indirectly via other immune system cells is not clear yet. In addition, the findings need to be replicated in more animals before this approach is tested in people. Nevertheless, the intravenous injection of cells of this type could provide a two-pronged approach to the treatment of MS (and other neuroinflammatory diseases). First, bone marrow–derived myeloid precursor cells that have been engineered to express TREM2 could help to treat MS by clearing tissue debris and reducing inflammation in spinal cord lesions. Second, the same cells could be used to deliver agents to the lesions that promote nerve repair. Importantly, these results suggest that TREM2-expressing myeloid precursor cells might have the potential to treat MS after the onset of clinical symptoms, an important consideration for a chronic disease that often indicates relapses by new clinical symptoms.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040124.
US National Institute of Neurological Disorders and Stroke patient information on multiple sclerosis (in English and Spanish)
UK National Health Service health encyclopedia information on multiple sclerosis
MedlinePlus encyclopedia pages on multiple sclerosis
The US National MS Society information on multiple sclerosis for patients and professionals (in English and Spanish)
UK MS Society information on multiple sclerosis for patients and professionals
Multiple Sclerosis International Federation information on multiple sclerosis for patients, caregivers, and professionals (in English, Arabic, German, Spanish, French, Italian and Russian)