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Modulation of microglial/macrophage activation by macrophage inhibitory factor (TKP) or tuftsin (TKPR) attenuates the disease course of experimental autoimmune encephalomyelitis.

Bhasin M, Wu M, Tsirka SE - BMC Immunol. (2007)

Bottom Line: Myelin Oligodendrocyte Glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) is the most commonly used mouse model for multiple sclerosis (MS).Microglial activation is mediated by the extracellular protease tissue Plasminogen Activator (tPA), and mice lacking tPA display altered EAE progression.Specific molecular targets have been identified that represent potential avenues of exploration for the treatment and prevention of MS.

View Article: PubMed Central - HTML - PubMed

Affiliation: Genetics, Department of Pharmacological Sciences, University Medical Center at Stony Brook, Stony Brook, NY 11794-8651, USA. bhasin@pharm.stonybrook.edu <bhasin@pharm.stonybrook.edu>

ABSTRACT

Background: Myelin Oligodendrocyte Glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) is the most commonly used mouse model for multiple sclerosis (MS). During the of progression of EAE, microglia, the immunocompetent cells of the brain, become activated and accumulate around demyelinated lesions. Microglial activation is mediated by the extracellular protease tissue Plasminogen Activator (tPA), and mice lacking tPA display altered EAE progression. In this study, we have used pharmacological inhibitors and stimulators of microglial/macrophage activation to examine the temporal requirement for microglial activation in EAE progression and to determine whether such approaches might potentially be of therapeutic value.

Results: Intervention using the tripeptide macrophage/microglia inhibitory factor MIF (TKP) and the tetrapeptide macrophage/microglial stimulator tuftsin (TKPR) attenuated EAE symptoms and revealed that the timing of macrophage/microglial activation is critical for the clinical outcome of EAE. We show that the disease progression can potentially be manipulated favorably at early stages by altering the timing of microglial activation, which in turn alters the systemic immune response to favor upregulation of T helper cell 2 genes that promote recovery from EAE.

Conclusion: Preventative and therapeutic modulation of macrophage/microglial activity significantly alters the outcome of EAE at symptomatic stages. Specific molecular targets have been identified that represent potential avenues of exploration for the treatment and prevention of MS.

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Prophylactic tuftsin infusion at day -1 in tPA-/- mice results in a dramatically early onset of EAE. (A) Disease onset occurs at day 3 in tPA-/- tufd-1 mice, much earlier than wt PBS (p = 0.03). Severity is dramatically decreased (p = 0.03) and recovery remained at a low level (p = 0.08). wt PBS n= 18, tPA-/- tufd-1 n = 11. (B) Luxol Fast Blue staining to visualize levels of demyelination. The dashed line and the asterisk demarcate the ventral column of the spinal cord. The intensity of luxol fast blue staining within the ventral column was quantified using the NIH Image freeware and was normalized to day 0 staining. Background staining was subtracted. (C) F4/80 immunohistochemistry for activated macrophages/microglia. (D) Immunohistochemistry for infiltrating T cells using an anti-CD3 antibody.
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Figure 5: Prophylactic tuftsin infusion at day -1 in tPA-/- mice results in a dramatically early onset of EAE. (A) Disease onset occurs at day 3 in tPA-/- tufd-1 mice, much earlier than wt PBS (p = 0.03). Severity is dramatically decreased (p = 0.03) and recovery remained at a low level (p = 0.08). wt PBS n= 18, tPA-/- tufd-1 n = 11. (B) Luxol Fast Blue staining to visualize levels of demyelination. The dashed line and the asterisk demarcate the ventral column of the spinal cord. The intensity of luxol fast blue staining within the ventral column was quantified using the NIH Image freeware and was normalized to day 0 staining. Background staining was subtracted. (C) F4/80 immunohistochemistry for activated macrophages/microglia. (D) Immunohistochemistry for infiltrating T cells using an anti-CD3 antibody.

Mentions: Prophylactic administration of tuftsin to tPA-/- mice resulted in early onset (d3) of EAE-like symptoms (Fig. 5A) in comparison to PBS-treated wt mice (onset at day 7) or tPA-/- mice (onset at day 10, data not shown). Despite the early onset, however, a blunted disease progression was observed, i.e. the symptoms never achieved the degree of severity observed in PBS-treated mice.


Modulation of microglial/macrophage activation by macrophage inhibitory factor (TKP) or tuftsin (TKPR) attenuates the disease course of experimental autoimmune encephalomyelitis.

Bhasin M, Wu M, Tsirka SE - BMC Immunol. (2007)

Prophylactic tuftsin infusion at day -1 in tPA-/- mice results in a dramatically early onset of EAE. (A) Disease onset occurs at day 3 in tPA-/- tufd-1 mice, much earlier than wt PBS (p = 0.03). Severity is dramatically decreased (p = 0.03) and recovery remained at a low level (p = 0.08). wt PBS n= 18, tPA-/- tufd-1 n = 11. (B) Luxol Fast Blue staining to visualize levels of demyelination. The dashed line and the asterisk demarcate the ventral column of the spinal cord. The intensity of luxol fast blue staining within the ventral column was quantified using the NIH Image freeware and was normalized to day 0 staining. Background staining was subtracted. (C) F4/80 immunohistochemistry for activated macrophages/microglia. (D) Immunohistochemistry for infiltrating T cells using an anti-CD3 antibody.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1937009&req=5

Figure 5: Prophylactic tuftsin infusion at day -1 in tPA-/- mice results in a dramatically early onset of EAE. (A) Disease onset occurs at day 3 in tPA-/- tufd-1 mice, much earlier than wt PBS (p = 0.03). Severity is dramatically decreased (p = 0.03) and recovery remained at a low level (p = 0.08). wt PBS n= 18, tPA-/- tufd-1 n = 11. (B) Luxol Fast Blue staining to visualize levels of demyelination. The dashed line and the asterisk demarcate the ventral column of the spinal cord. The intensity of luxol fast blue staining within the ventral column was quantified using the NIH Image freeware and was normalized to day 0 staining. Background staining was subtracted. (C) F4/80 immunohistochemistry for activated macrophages/microglia. (D) Immunohistochemistry for infiltrating T cells using an anti-CD3 antibody.
Mentions: Prophylactic administration of tuftsin to tPA-/- mice resulted in early onset (d3) of EAE-like symptoms (Fig. 5A) in comparison to PBS-treated wt mice (onset at day 7) or tPA-/- mice (onset at day 10, data not shown). Despite the early onset, however, a blunted disease progression was observed, i.e. the symptoms never achieved the degree of severity observed in PBS-treated mice.

Bottom Line: Myelin Oligodendrocyte Glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) is the most commonly used mouse model for multiple sclerosis (MS).Microglial activation is mediated by the extracellular protease tissue Plasminogen Activator (tPA), and mice lacking tPA display altered EAE progression.Specific molecular targets have been identified that represent potential avenues of exploration for the treatment and prevention of MS.

View Article: PubMed Central - HTML - PubMed

Affiliation: Genetics, Department of Pharmacological Sciences, University Medical Center at Stony Brook, Stony Brook, NY 11794-8651, USA. bhasin@pharm.stonybrook.edu <bhasin@pharm.stonybrook.edu>

ABSTRACT

Background: Myelin Oligodendrocyte Glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) is the most commonly used mouse model for multiple sclerosis (MS). During the of progression of EAE, microglia, the immunocompetent cells of the brain, become activated and accumulate around demyelinated lesions. Microglial activation is mediated by the extracellular protease tissue Plasminogen Activator (tPA), and mice lacking tPA display altered EAE progression. In this study, we have used pharmacological inhibitors and stimulators of microglial/macrophage activation to examine the temporal requirement for microglial activation in EAE progression and to determine whether such approaches might potentially be of therapeutic value.

Results: Intervention using the tripeptide macrophage/microglia inhibitory factor MIF (TKP) and the tetrapeptide macrophage/microglial stimulator tuftsin (TKPR) attenuated EAE symptoms and revealed that the timing of macrophage/microglial activation is critical for the clinical outcome of EAE. We show that the disease progression can potentially be manipulated favorably at early stages by altering the timing of microglial activation, which in turn alters the systemic immune response to favor upregulation of T helper cell 2 genes that promote recovery from EAE.

Conclusion: Preventative and therapeutic modulation of macrophage/microglial activity significantly alters the outcome of EAE at symptomatic stages. Specific molecular targets have been identified that represent potential avenues of exploration for the treatment and prevention of MS.

Show MeSH
Related in: MedlinePlus