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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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Related in: MedlinePlus

Prophylactic administration of Tuftsin in wild-type mice results in a dampened disease course. (A) Disease onset in wt tufd-1 mice does not differ from wt PBS mice. Severity is dramatically decreased (p = 0.008) and recovery is complete (p = 0.016). wt PBS n= 18, wt tufd-1 n = 13. (B) Luxol fast blue histological stain reveals levels of myelination. 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) Reactive macrophages/microglia are visible in the coronal sections of experimental mice at different timepoints. (D) Infiltrating T cells were detected by immunohistochemistry using an anti-CD3 antibody.
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Figure 3: Prophylactic administration of Tuftsin in wild-type mice results in a dampened disease course. (A) Disease onset in wt tufd-1 mice does not differ from wt PBS mice. Severity is dramatically decreased (p = 0.008) and recovery is complete (p = 0.016). wt PBS n= 18, wt tufd-1 n = 13. (B) Luxol fast blue histological stain reveals levels of myelination. 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) Reactive macrophages/microglia are visible in the coronal sections of experimental mice at different timepoints. (D) Infiltrating T cells were detected by immunohistochemistry using an anti-CD3 antibody.

Mentions: Infusion of tuftsin one day prior to induction of EAE (tuf) resulted in decreased symptom severity and earlier recovery, although the day of onset was unaffected (Fig. 3A). The symptoms plateaued at a low level (clinical score of 1) before complete recovery was observed around day 29.


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 administration of Tuftsin in wild-type mice results in a dampened disease course. (A) Disease onset in wt tufd-1 mice does not differ from wt PBS mice. Severity is dramatically decreased (p = 0.008) and recovery is complete (p = 0.016). wt PBS n= 18, wt tufd-1 n = 13. (B) Luxol fast blue histological stain reveals levels of myelination. 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) Reactive macrophages/microglia are visible in the coronal sections of experimental mice at different timepoints. (D) Infiltrating T cells were detected by immunohistochemistry using an anti-CD3 antibody.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Prophylactic administration of Tuftsin in wild-type mice results in a dampened disease course. (A) Disease onset in wt tufd-1 mice does not differ from wt PBS mice. Severity is dramatically decreased (p = 0.008) and recovery is complete (p = 0.016). wt PBS n= 18, wt tufd-1 n = 13. (B) Luxol fast blue histological stain reveals levels of myelination. 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) Reactive macrophages/microglia are visible in the coronal sections of experimental mice at different timepoints. (D) Infiltrating T cells were detected by immunohistochemistry using an anti-CD3 antibody.
Mentions: Infusion of tuftsin one day prior to induction of EAE (tuf) resulted in decreased symptom severity and earlier recovery, although the day of onset was unaffected (Fig. 3A). The symptoms plateaued at a low level (clinical score of 1) before complete recovery was observed around day 29.

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