TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Takahashi
Kazuya
K
Neural Regeneration Unit, Institute of Reconstructive Neurobiology, University of Bonn Life & Brain Center and Hertie-Foundation, Bonn, Germany.
Prinz
Marco
M
Stagi
Massimiliano
M
Chechneva
Olga
O
Neumann
Harald
H
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage; D002465:Cell Movement; D002478:Cells, Cultured / Q000502:physiology / Q000637:transplantation; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005813:Genes, Synthetic; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D016086:Lentivirus / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000502:physiology*; D009000:Monocytes / Q000502:physiology; D009103:Multiple Sclerosis; D022423:Myeloid Cells / Q000187:drug effects / Q000502:physiology / Q000637:transplantation*; D009474:Neurons / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics; D010587:Phagocytosis; D011401:Promoter Regions, Genetic; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology*; D014161:Transduction, Genetic
D016207:Cytokines; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498716:Trem2 protein, mouse; D016753:Interleukin-10; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse