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

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.

IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation

“…Loss of TREM2 function impairs microglial phagocytosis (51,52), and enhanced TREM2-dependent phagocytosis of degenerated myelin can ameliorate EAE (51). TREM2 is known to interact with the signaling adapter protein DAP12 (DNAX-activation protein of 12 kDa) (53); however its ligand in apoptotic cells and other cellular debris is unknown.…”

Efficient colonic mucosal wound repair requires Trem2 signaling

“…First, Trem2 is a cell surface receptor (with as yet undetermined ligand) that is specifically induced in macrophages by IL-4/IL-13. Second, Trem2 signaling is important in injury responses (21)(22)(23)(24)(25)(26). In situations where low levels of TLR ligands are present, Trem2 suppresses TLR signaling (23,24).…”

Juzen-taiho-to, an Herbal Medicine, Activates and Enhances Phagocytosis in Microglia/Macrophages

“…The other group (control group, n = 4) was given plain drinking water. After 21 days, isolation of BMM was performed by a modified method published by Takahashi and collaborators (Takahashi et al 2007). In detail, the mice were sacrificed by decapitation and bone marrow cells were freshly flushed from the medullary cavities of the femurs and tibias with a 25 ga needle, and then filtered through a 40 μ m nylon mesh.…”