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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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Expression Profile of TREM2 in Normal and Diseased CNS(A) Flow cytometry analysis of TREM2 (open tracings) expression on CD11b+ cells derived from the cortex of normal and EAE-diseased mice at day 4 after onset of clinical symptoms as well as from EAE-diseased mice at day 18 after onset of clinical symptoms. Isotype controls are shown in grey-filled tracings. TREM2 expression is detected on CD11b+ microglia/macrophages in the cortex of EAE-diseased mice. The percentages of TREM2+ cells are indicated in the upper-right corner of each histogram. Selected representative histograms are shown.(B) Quantitative analysis of TREM2 expression on microglia by flow cytometry gated for CD11b+ cells. TREM2 expression is detected only on a minority of microglia and perivascular macrophages in the normal CNS tissue, but is up-regulated and detected in the spinal cord on the majority of CD11b+ cells at day 4 after onset of clinical symptoms of EAE. Data are presented as mean ± SEM. Tissues were derived from four EAE and four normal mice.
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pmed-0040124-g001: Expression Profile of TREM2 in Normal and Diseased CNS(A) Flow cytometry analysis of TREM2 (open tracings) expression on CD11b+ cells derived from the cortex of normal and EAE-diseased mice at day 4 after onset of clinical symptoms as well as from EAE-diseased mice at day 18 after onset of clinical symptoms. Isotype controls are shown in grey-filled tracings. TREM2 expression is detected on CD11b+ microglia/macrophages in the cortex of EAE-diseased mice. The percentages of TREM2+ cells are indicated in the upper-right corner of each histogram. Selected representative histograms are shown.(B) Quantitative analysis of TREM2 expression on microglia by flow cytometry gated for CD11b+ cells. TREM2 expression is detected only on a minority of microglia and perivascular macrophages in the normal CNS tissue, but is up-regulated and detected in the spinal cord on the majority of CD11b+ cells at day 4 after onset of clinical symptoms of EAE. Data are presented as mean ± SEM. Tissues were derived from four EAE and four normal mice.

Mentions: TREM2 has been shown to be expressed on certain subtypes of myeloid cells, particularly osteoclasts, immature dendritic cells, and microglia [21]. To study the expression kinetics of TREM2 during EAE, we performed flow cytometry analysis of TREM2 on freshly isolated microglia and resident CNS cells identified by immmunostaining for CD11b. Flow cytometry analysis demonstrated TREM2 expression on a minority of microglial cells under normal conditions in adult C57BL/6 mice (Figure 1A). Next, we induced EAE by immunization with the myelin oligodendrocyte glycoprotein peptide 35–55. At day 4 after onset of clinical symptoms of EAE, TREM2 was detected on approximately half of the CD11b+ cells in the spinal cord, the tissue region mostly affected by the inflammatory lesions (Figure 1A and 1B). In detail, the percentage of TREM2 and CD11b+ cells in the spinal cord increased from 23.3% (standard error of the mean [SEM] 16.1) in the normal tissue to 58.8% (SEM 4.2) at day 4 after onset of clinical signs of the disease (Figure 1B). The up-regulation of TREM2 was detected mainly in the spinal cord, but not in the cortex and cerebellum, indicating that TREM2 expression is associated with the inflammatory lesions. The up-regulation of TREM2 on CD11b+ cells was not long lasting and returned back to almost normal levels at day 18 after onset of clinical EAE symptoms (Figure 1B).


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)

Expression Profile of TREM2 in Normal and Diseased CNS(A) Flow cytometry analysis of TREM2 (open tracings) expression on CD11b+ cells derived from the cortex of normal and EAE-diseased mice at day 4 after onset of clinical symptoms as well as from EAE-diseased mice at day 18 after onset of clinical symptoms. Isotype controls are shown in grey-filled tracings. TREM2 expression is detected on CD11b+ microglia/macrophages in the cortex of EAE-diseased mice. The percentages of TREM2+ cells are indicated in the upper-right corner of each histogram. Selected representative histograms are shown.(B) Quantitative analysis of TREM2 expression on microglia by flow cytometry gated for CD11b+ cells. TREM2 expression is detected only on a minority of microglia and perivascular macrophages in the normal CNS tissue, but is up-regulated and detected in the spinal cord on the majority of CD11b+ cells at day 4 after onset of clinical symptoms of EAE. Data are presented as mean ± SEM. Tissues were derived from four EAE and four normal mice.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC1851623&req=5

pmed-0040124-g001: Expression Profile of TREM2 in Normal and Diseased CNS(A) Flow cytometry analysis of TREM2 (open tracings) expression on CD11b+ cells derived from the cortex of normal and EAE-diseased mice at day 4 after onset of clinical symptoms as well as from EAE-diseased mice at day 18 after onset of clinical symptoms. Isotype controls are shown in grey-filled tracings. TREM2 expression is detected on CD11b+ microglia/macrophages in the cortex of EAE-diseased mice. The percentages of TREM2+ cells are indicated in the upper-right corner of each histogram. Selected representative histograms are shown.(B) Quantitative analysis of TREM2 expression on microglia by flow cytometry gated for CD11b+ cells. TREM2 expression is detected only on a minority of microglia and perivascular macrophages in the normal CNS tissue, but is up-regulated and detected in the spinal cord on the majority of CD11b+ cells at day 4 after onset of clinical symptoms of EAE. Data are presented as mean ± SEM. Tissues were derived from four EAE and four normal mice.
Mentions: TREM2 has been shown to be expressed on certain subtypes of myeloid cells, particularly osteoclasts, immature dendritic cells, and microglia [21]. To study the expression kinetics of TREM2 during EAE, we performed flow cytometry analysis of TREM2 on freshly isolated microglia and resident CNS cells identified by immmunostaining for CD11b. Flow cytometry analysis demonstrated TREM2 expression on a minority of microglial cells under normal conditions in adult C57BL/6 mice (Figure 1A). Next, we induced EAE by immunization with the myelin oligodendrocyte glycoprotein peptide 35–55. At day 4 after onset of clinical symptoms of EAE, TREM2 was detected on approximately half of the CD11b+ cells in the spinal cord, the tissue region mostly affected by the inflammatory lesions (Figure 1A and 1B). In detail, the percentage of TREM2 and CD11b+ cells in the spinal cord increased from 23.3% (standard error of the mean [SEM] 16.1) in the normal tissue to 58.8% (SEM 4.2) at day 4 after onset of clinical signs of the disease (Figure 1B). The up-regulation of TREM2 was detected mainly in the spinal cord, but not in the cortex and cerebellum, indicating that TREM2 expression is associated with the inflammatory lesions. The up-regulation of TREM2 on CD11b+ cells was not long lasting and returned back to almost normal levels at day 18 after onset of clinical EAE symptoms (Figure 1B).

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