Research Article: TREM2-Transduced Myeloid Precursors Mediate Nervous Tissue Debris Clearance and Facilitate Recovery in an Animal Model of Multiple Sclerosis

Date Published: April 10, 2007

Publisher: Public Library of Science

Author(s): Kazuya Takahashi, Marco Prinz, Massimiliano Stagi, Olga Chechneva, Harald Neumann, Manuel Graeber

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.

Partial Text: Hematopoietic-derived myeloid cells physiologically migrate into the central nervous system (CNS) not only during development, but also in adulthood, and become resident perivascular macrophages and microglia [1–3]. Data suggest that there is a continuous and lifelong turnover of perivascular brain macrophages replenished by bone marrow–derived cells. Furthermore, it has been demonstrated that bone marrow cells are recruited to sites of axonal degeneration [4,5] or to beta-amyloid depositions in Alzheimer disease animal models [6,7] to become functional microglia-like cells. The exact cellular subtype of myeloid precursors developing into microglia is not known, but parenchymal microglial cells have been reported to be phenotypically very similar to uncommitted myeloid precursors having “empty” major histocompatibility complex (MHC) class II, comparable cystein protease profiles, and the capacity to differentiate into dendritic-like cells [8,9]. Thus, bone marrow–derived myeloid cells (BM-MC) might reflect microglial precursors and may serve as a natural vehicle for CNS cell and gene therapy [2,10].

In this study, we have shown that intravenously applied TREM2-transduced myeloid precursors ameliorate clinical symptoms and induce recovery from EAE. The TREM2-transduced myeloid cells migrated into the CNS lesions, induced myelin debris clearance, and created an anti-inflammatory cytokine milieu. The treated mice showed less axonal injury and reduced demyelination. The data demonstrate that TREM2+ myeloid cells are involved in tissue debris clearance and resolution of inflammation and suggest a novel approach to the therapy of neuroinflammatory disease.



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