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

Takahashi K, Prinz M, Stagi M, Chechneva O, Neumann H - PLoS Med. (2007)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Neural Regeneration Unit, Institute of Reconstructive Neurobiology, University of Bonn Life & Brain Center and Hertie-Foundation, Bonn, Germany.

ABSTRACT

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.

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.

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.

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TREM2-Transduced Myeloid Cells Ameliorated EAE(A) Treatment of EAE-diseased mice by TREM2-transduced myeloid cells at the peak of the disease. Clinical EAE score of mice injected at day 4 after first clinical signs of the disease (arrow) with TREM2-transduced myeloid cells (black tracing), control GFP vector–transduced myeloid cells (green tracing), or PBS (red tracing). Intravenous application of 5 × 106 TREM2-transduced myeloid cells ameliorated the clinical score of EAE. Data are presented as mean ± SD. Mice per group: n = 6 or n = 7. ANOVA followed by unpaired t-test: p = 0.0015 (TREM2 versus GFP) and p = 0.0063 (TREM2 versus PBS) at day 20; p = 0.0045 (TREM2 versus GFP) and p = 0.0046 (TREM2 versus PBS) at day 30.(B) TREM2-transduced myeloid cells injected at the onset of the disease do not affect EAE. Clinical EAE score of mice injected 1 d after the first clinical signs of the disease (arrow) with 5 × 106 TREM2-transduced myeloid cells (black), 5 × 106 control GFP vector–transduced myeloid cells (green), or PBS (red). No effect on the clinical EAE score was observed. Data are presented as mean ± SD. Mice per group: n = 3.(C) Treatment of EAE by TREM2-transduced myeloid cells. Clinical EAE score of mice injected at day 4 after first clinical signs of the disease with 2 × 106 TREM2-transduced myeloid cells (black), 5 × 106 TREM2-transduced myeloid cells (grey), or PBS control (red). Intravenous application of 2 × 106 or 5 × 106 TREM2-transduced myeloid cells ameliorated the clinical score of EAE. Data are presented as mean ± SD. Mice per group: n = 3. ANOVA followed by unpaired t-test: p = 0.0023 (2 × 106 cells versus PBS) and p = 0.0068 (5 × 106 cells versus PBS) at day 20; p = 0.0107 (2 × 106 cells versus PBS) at day 30.
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pmed-0040124-g006: TREM2-Transduced Myeloid Cells Ameliorated EAE(A) Treatment of EAE-diseased mice by TREM2-transduced myeloid cells at the peak of the disease. Clinical EAE score of mice injected at day 4 after first clinical signs of the disease (arrow) with TREM2-transduced myeloid cells (black tracing), control GFP vector–transduced myeloid cells (green tracing), or PBS (red tracing). Intravenous application of 5 × 106 TREM2-transduced myeloid cells ameliorated the clinical score of EAE. Data are presented as mean ± SD. Mice per group: n = 6 or n = 7. ANOVA followed by unpaired t-test: p = 0.0015 (TREM2 versus GFP) and p = 0.0063 (TREM2 versus PBS) at day 20; p = 0.0045 (TREM2 versus GFP) and p = 0.0046 (TREM2 versus PBS) at day 30.(B) TREM2-transduced myeloid cells injected at the onset of the disease do not affect EAE. Clinical EAE score of mice injected 1 d after the first clinical signs of the disease (arrow) with 5 × 106 TREM2-transduced myeloid cells (black), 5 × 106 control GFP vector–transduced myeloid cells (green), or PBS (red). No effect on the clinical EAE score was observed. Data are presented as mean ± SD. Mice per group: n = 3.(C) Treatment of EAE by TREM2-transduced myeloid cells. Clinical EAE score of mice injected at day 4 after first clinical signs of the disease with 2 × 106 TREM2-transduced myeloid cells (black), 5 × 106 TREM2-transduced myeloid cells (grey), or PBS control (red). Intravenous application of 2 × 106 or 5 × 106 TREM2-transduced myeloid cells ameliorated the clinical score of EAE. Data are presented as mean ± SD. Mice per group: n = 3. ANOVA followed by unpaired t-test: p = 0.0023 (2 × 106 cells versus PBS) and p = 0.0068 (5 × 106 cells versus PBS) at day 20; p = 0.0107 (2 × 106 cells versus PBS) at day 30.

Mentions: TREM2-transduced BM-MC showed an effect on the EAE disease course, leading to early and almost complete recovery from clinical symptoms. In total, 5 × 106 BM-MC were injected intravenously at day 4 after onset of first clinical symptoms of EAE, which coincides with the disease peak with ongoing tissue destruction. Already 2 days after cell injection, mice improved in clinical performance (Figure 6A). At 7 days, the mean clinical score was reduced from 2.5 (SD 0.4) after GFP-transduced BM-MC application to 1.3 (SD 0.1) after TREM2-transduced BM-MC application (Figure 6A; Table S2). While no difference was detectable in the cumulative clinical score before and on the day of cell injection, the cumulative clinical score was reduced from 33.8 (SD 2.5) after injection of 5 × 106 GFP-transduced BM-MC to 17.6 (SD 6.0) after injection of 5 × 106 TREM2-transduced BM-MC (Table S2). Importantly, no changes in either the disease course or in cumulative clinical scores were observed in PBS-injected mice and control GFP vector–transduced BM-MC–injected animals (Table S2). TREM2-transduced BM-MC were only effective in ameliorating the disease symptoms if injected at day 4 after onset of clinical symptoms. TREM2-transduced cells injected at day 1 after clinical onset of EAE did not interfere with the disease course, indicating that TREM2-tranduced BM-MC do not prevent the initiation phase of EAE, but act during the recovery and repair phase of the disease (Figure 6B). Finally, we analyzed the effect of different cell amounts of TREM2-transduced BM-MC. A reduced cell amount of 2 × 106 TREM2-transduced BM-MC was as effective in ameliorating the clinical disease course as 5 × 106 TREM2-transduced BM-MC (Figure 6C).


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

Takahashi K, Prinz M, Stagi M, Chechneva O, Neumann H - PLoS Med. (2007)

TREM2-Transduced Myeloid Cells Ameliorated EAE(A) Treatment of EAE-diseased mice by TREM2-transduced myeloid cells at the peak of the disease. Clinical EAE score of mice injected at day 4 after first clinical signs of the disease (arrow) with TREM2-transduced myeloid cells (black tracing), control GFP vector–transduced myeloid cells (green tracing), or PBS (red tracing). Intravenous application of 5 × 106 TREM2-transduced myeloid cells ameliorated the clinical score of EAE. Data are presented as mean ± SD. Mice per group: n = 6 or n = 7. ANOVA followed by unpaired t-test: p = 0.0015 (TREM2 versus GFP) and p = 0.0063 (TREM2 versus PBS) at day 20; p = 0.0045 (TREM2 versus GFP) and p = 0.0046 (TREM2 versus PBS) at day 30.(B) TREM2-transduced myeloid cells injected at the onset of the disease do not affect EAE. Clinical EAE score of mice injected 1 d after the first clinical signs of the disease (arrow) with 5 × 106 TREM2-transduced myeloid cells (black), 5 × 106 control GFP vector–transduced myeloid cells (green), or PBS (red). No effect on the clinical EAE score was observed. Data are presented as mean ± SD. Mice per group: n = 3.(C) Treatment of EAE by TREM2-transduced myeloid cells. Clinical EAE score of mice injected at day 4 after first clinical signs of the disease with 2 × 106 TREM2-transduced myeloid cells (black), 5 × 106 TREM2-transduced myeloid cells (grey), or PBS control (red). Intravenous application of 2 × 106 or 5 × 106 TREM2-transduced myeloid cells ameliorated the clinical score of EAE. Data are presented as mean ± SD. Mice per group: n = 3. ANOVA followed by unpaired t-test: p = 0.0023 (2 × 106 cells versus PBS) and p = 0.0068 (5 × 106 cells versus PBS) at day 20; p = 0.0107 (2 × 106 cells versus PBS) at day 30.
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pmed-0040124-g006: TREM2-Transduced Myeloid Cells Ameliorated EAE(A) Treatment of EAE-diseased mice by TREM2-transduced myeloid cells at the peak of the disease. Clinical EAE score of mice injected at day 4 after first clinical signs of the disease (arrow) with TREM2-transduced myeloid cells (black tracing), control GFP vector–transduced myeloid cells (green tracing), or PBS (red tracing). Intravenous application of 5 × 106 TREM2-transduced myeloid cells ameliorated the clinical score of EAE. Data are presented as mean ± SD. Mice per group: n = 6 or n = 7. ANOVA followed by unpaired t-test: p = 0.0015 (TREM2 versus GFP) and p = 0.0063 (TREM2 versus PBS) at day 20; p = 0.0045 (TREM2 versus GFP) and p = 0.0046 (TREM2 versus PBS) at day 30.(B) TREM2-transduced myeloid cells injected at the onset of the disease do not affect EAE. Clinical EAE score of mice injected 1 d after the first clinical signs of the disease (arrow) with 5 × 106 TREM2-transduced myeloid cells (black), 5 × 106 control GFP vector–transduced myeloid cells (green), or PBS (red). No effect on the clinical EAE score was observed. Data are presented as mean ± SD. Mice per group: n = 3.(C) Treatment of EAE by TREM2-transduced myeloid cells. Clinical EAE score of mice injected at day 4 after first clinical signs of the disease with 2 × 106 TREM2-transduced myeloid cells (black), 5 × 106 TREM2-transduced myeloid cells (grey), or PBS control (red). Intravenous application of 2 × 106 or 5 × 106 TREM2-transduced myeloid cells ameliorated the clinical score of EAE. Data are presented as mean ± SD. Mice per group: n = 3. ANOVA followed by unpaired t-test: p = 0.0023 (2 × 106 cells versus PBS) and p = 0.0068 (5 × 106 cells versus PBS) at day 20; p = 0.0107 (2 × 106 cells versus PBS) at day 30.
Mentions: TREM2-transduced BM-MC showed an effect on the EAE disease course, leading to early and almost complete recovery from clinical symptoms. In total, 5 × 106 BM-MC were injected intravenously at day 4 after onset of first clinical symptoms of EAE, which coincides with the disease peak with ongoing tissue destruction. Already 2 days after cell injection, mice improved in clinical performance (Figure 6A). At 7 days, the mean clinical score was reduced from 2.5 (SD 0.4) after GFP-transduced BM-MC application to 1.3 (SD 0.1) after TREM2-transduced BM-MC application (Figure 6A; Table S2). While no difference was detectable in the cumulative clinical score before and on the day of cell injection, the cumulative clinical score was reduced from 33.8 (SD 2.5) after injection of 5 × 106 GFP-transduced BM-MC to 17.6 (SD 6.0) after injection of 5 × 106 TREM2-transduced BM-MC (Table S2). Importantly, no changes in either the disease course or in cumulative clinical scores were observed in PBS-injected mice and control GFP vector–transduced BM-MC–injected animals (Table S2). TREM2-transduced BM-MC were only effective in ameliorating the disease symptoms if injected at day 4 after onset of clinical symptoms. TREM2-transduced cells injected at day 1 after clinical onset of EAE did not interfere with the disease course, indicating that TREM2-tranduced BM-MC do not prevent the initiation phase of EAE, but act during the recovery and repair phase of the disease (Figure 6B). Finally, we analyzed the effect of different cell amounts of TREM2-transduced BM-MC. A reduced cell amount of 2 × 106 TREM2-transduced BM-MC was as effective in ameliorating the clinical disease course as 5 × 106 TREM2-transduced BM-MC (Figure 6C).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Neural Regeneration Unit, Institute of Reconstructive Neurobiology, University of Bonn Life & Brain Center and Hertie-Foundation, Bonn, Germany.

ABSTRACT

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.

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.

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.

Show MeSH
Related in: MedlinePlus