Abstract
BackgroundIn 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 FindingsEAE 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.ConclusionsIntravenously 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.
Highlights
Hematopoietic-derived myeloid cells physiologically migrate into the central nervous system (CNS) during development, and in adulthood, and become resident perivascular macrophages and microglia [1,2,3]
We investigated whether myeloid precursor cells genetically modified to express triggering receptor expressed on myeloid cells 2 (TREM2) affect the disease course of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis
TREM2 has been shown to be expressed on certain subtypes of myeloid cells, osteoclasts, immature dendritic cells, and microglia [21]
Summary
Hematopoietic-derived myeloid cells physiologically migrate into the central nervous system (CNS) during development, and in adulthood, and become resident perivascular macrophages and microglia [1,2,3]. We discovered in vitro that the microglial triggering receptor expressed on myeloid cells-2 (TREM2) stimulates phagocytosis and down-regulates inflammatory signals in microglia via the signaling adaptor molecule DAP12 [14]. Both clearance of tissue debris by phagocytosis and a protective cytokine milieu have been implicated as positive factors for tissue repair in multiple sclerosis (MS) [15]. 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. There is no cure for MS, but drugs that modulate the immune system (for example, interferons and steroids) can slow its progression
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