Limits...
Astrocyte matricellular proteins that control excitatory synaptogenesis are regulated by inflammatory cytokines and correlate with paralysis severity during experimental autoimmune encephalomyelitis.

Blakely PK, Hussain S, Carlin LE, Irani DN - Front Neurosci (2015)

Bottom Line: Taken together, these data support a model whereby proinflammatory cytokines inhibit SPARCL1 and/or augment SPARC expression by astrocytes in spinal gray matter that, in turn, cause either transient or sustained synaptic retraction from lumbar spinal motor neurons thereby regulating hind limb paralysis during EAE.Ongoing studies seek ways to alter this SPARCL1:SPARC expression ratio in favor of synapse reformation/maintenance and thus help to modulate neurologic deficits during times of inflammation.This could identify new astrocyte-targeted therapies for diseases such as multiple sclerosis.

View Article: PubMed Central - PubMed

Affiliation: Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan Medical School Ann Arbor, MI, USA.

ABSTRACT
The matricellular proteins, secreted protein acidic and rich in cysteine (SPARC) and SPARC-like 1 (SPARCL1), are produced by astrocytes and control excitatory synaptogenesis in the central nervous system. While SPARCL1 directly promotes excitatory synapse formation in vitro and in the developing nervous system in vivo, SPARC specifically antagonizes the synaptogenic actions of SPARCL1. We hypothesized these proteins also help maintain existing excitatory synapses in adult hosts, and that local inflammation in the spinal cord alters their production in a way that dynamically modulates motor synapses and impacts the severity of paralysis during experimental autoimmune encephalomyelitis (EAE) in mice. Using a spontaneously remitting EAE model, paralysis severity correlated inversely with both expression of synaptic proteins and the number of synapses in direct contact with the perikarya of motor neurons in spinal gray matter. In both remitting and non-remitting EAE models, paralysis severity also correlated inversely with sparcl1:sparc transcript and SPARCL1:SPARC protein ratios directly in lumbar spinal cord tissue. In vitro, astrocyte production of both SPARCL1 and SPARC was regulated by T cell-derived cytokines, causing dynamic modulation of the SPARCL1:SPARC expression ratio. Taken together, these data support a model whereby proinflammatory cytokines inhibit SPARCL1 and/or augment SPARC expression by astrocytes in spinal gray matter that, in turn, cause either transient or sustained synaptic retraction from lumbar spinal motor neurons thereby regulating hind limb paralysis during EAE. Ongoing studies seek ways to alter this SPARCL1:SPARC expression ratio in favor of synapse reformation/maintenance and thus help to modulate neurologic deficits during times of inflammation. This could identify new astrocyte-targeted therapies for diseases such as multiple sclerosis.

No MeSH data available.


Related in: MedlinePlus

Expression of sparcl1 and sparc transcripts and SPARCL1 and SPARC proteins changes in lumbar spinal cord tissue over the course of non-relapsing EAE in C57BL/6 mice. (A,B) Representative immunofluorescence shows SPARCL1 expression co-localizes with GFAP staining in both white and gray matter of the spinal cord, Bar = 40 μm. (C) Relative sparcl1 mRNA expression fluxes over the course of non-relapsing EAE (n = 5 mice per disease stage). (D) Relative sparc mRNA expression does not change over the course of non-relapsing EAE (n = 5 mice per disease stage). (E) The calculated sparcl1 to sparc mRNA expression ratio shifts in favor of synapse inhibition at peak disease. (F) A similar change in the SPARCL1 to SPARC protein concentration ratios is seen over the course of non-relapsing EAE (n = 5 mice per disease stage). *p < 0.05 compared to levels found in naïve spinal cord.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4598482&req=5

Figure 5: Expression of sparcl1 and sparc transcripts and SPARCL1 and SPARC proteins changes in lumbar spinal cord tissue over the course of non-relapsing EAE in C57BL/6 mice. (A,B) Representative immunofluorescence shows SPARCL1 expression co-localizes with GFAP staining in both white and gray matter of the spinal cord, Bar = 40 μm. (C) Relative sparcl1 mRNA expression fluxes over the course of non-relapsing EAE (n = 5 mice per disease stage). (D) Relative sparc mRNA expression does not change over the course of non-relapsing EAE (n = 5 mice per disease stage). (E) The calculated sparcl1 to sparc mRNA expression ratio shifts in favor of synapse inhibition at peak disease. (F) A similar change in the SPARCL1 to SPARC protein concentration ratios is seen over the course of non-relapsing EAE (n = 5 mice per disease stage). *p < 0.05 compared to levels found in naïve spinal cord.

Mentions: When non-relapsing EAE was induced in C57BL/6 mice following immunization with the MOG35−55 peptide, SPARCL1 co-localized with GFAP expression in both gray and white matter (Figures 5A,B), and sparcl1 transcripts also declined in the lumbar spinal cord as mice transitioned from preclinical to peak disease (Figure 5C). In this setting, sparc levels did not change over time (Figure 5D), but the sparcl1:sparc transcript ratio and the SPARCL1:SPARC protein ratio also declined as disease symptoms became severe (Figures 5E,F). Together, these data show that factors present in the spinal cord suppress astrocyte production of synaptogenic proteins during peak EAE even as these cells assume an activated phenotype.


Astrocyte matricellular proteins that control excitatory synaptogenesis are regulated by inflammatory cytokines and correlate with paralysis severity during experimental autoimmune encephalomyelitis.

Blakely PK, Hussain S, Carlin LE, Irani DN - Front Neurosci (2015)

Expression of sparcl1 and sparc transcripts and SPARCL1 and SPARC proteins changes in lumbar spinal cord tissue over the course of non-relapsing EAE in C57BL/6 mice. (A,B) Representative immunofluorescence shows SPARCL1 expression co-localizes with GFAP staining in both white and gray matter of the spinal cord, Bar = 40 μm. (C) Relative sparcl1 mRNA expression fluxes over the course of non-relapsing EAE (n = 5 mice per disease stage). (D) Relative sparc mRNA expression does not change over the course of non-relapsing EAE (n = 5 mice per disease stage). (E) The calculated sparcl1 to sparc mRNA expression ratio shifts in favor of synapse inhibition at peak disease. (F) A similar change in the SPARCL1 to SPARC protein concentration ratios is seen over the course of non-relapsing EAE (n = 5 mice per disease stage). *p < 0.05 compared to levels found in naïve spinal cord.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4598482&req=5

Figure 5: Expression of sparcl1 and sparc transcripts and SPARCL1 and SPARC proteins changes in lumbar spinal cord tissue over the course of non-relapsing EAE in C57BL/6 mice. (A,B) Representative immunofluorescence shows SPARCL1 expression co-localizes with GFAP staining in both white and gray matter of the spinal cord, Bar = 40 μm. (C) Relative sparcl1 mRNA expression fluxes over the course of non-relapsing EAE (n = 5 mice per disease stage). (D) Relative sparc mRNA expression does not change over the course of non-relapsing EAE (n = 5 mice per disease stage). (E) The calculated sparcl1 to sparc mRNA expression ratio shifts in favor of synapse inhibition at peak disease. (F) A similar change in the SPARCL1 to SPARC protein concentration ratios is seen over the course of non-relapsing EAE (n = 5 mice per disease stage). *p < 0.05 compared to levels found in naïve spinal cord.
Mentions: When non-relapsing EAE was induced in C57BL/6 mice following immunization with the MOG35−55 peptide, SPARCL1 co-localized with GFAP expression in both gray and white matter (Figures 5A,B), and sparcl1 transcripts also declined in the lumbar spinal cord as mice transitioned from preclinical to peak disease (Figure 5C). In this setting, sparc levels did not change over time (Figure 5D), but the sparcl1:sparc transcript ratio and the SPARCL1:SPARC protein ratio also declined as disease symptoms became severe (Figures 5E,F). Together, these data show that factors present in the spinal cord suppress astrocyte production of synaptogenic proteins during peak EAE even as these cells assume an activated phenotype.

Bottom Line: Taken together, these data support a model whereby proinflammatory cytokines inhibit SPARCL1 and/or augment SPARC expression by astrocytes in spinal gray matter that, in turn, cause either transient or sustained synaptic retraction from lumbar spinal motor neurons thereby regulating hind limb paralysis during EAE.Ongoing studies seek ways to alter this SPARCL1:SPARC expression ratio in favor of synapse reformation/maintenance and thus help to modulate neurologic deficits during times of inflammation.This could identify new astrocyte-targeted therapies for diseases such as multiple sclerosis.

View Article: PubMed Central - PubMed

Affiliation: Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan Medical School Ann Arbor, MI, USA.

ABSTRACT
The matricellular proteins, secreted protein acidic and rich in cysteine (SPARC) and SPARC-like 1 (SPARCL1), are produced by astrocytes and control excitatory synaptogenesis in the central nervous system. While SPARCL1 directly promotes excitatory synapse formation in vitro and in the developing nervous system in vivo, SPARC specifically antagonizes the synaptogenic actions of SPARCL1. We hypothesized these proteins also help maintain existing excitatory synapses in adult hosts, and that local inflammation in the spinal cord alters their production in a way that dynamically modulates motor synapses and impacts the severity of paralysis during experimental autoimmune encephalomyelitis (EAE) in mice. Using a spontaneously remitting EAE model, paralysis severity correlated inversely with both expression of synaptic proteins and the number of synapses in direct contact with the perikarya of motor neurons in spinal gray matter. In both remitting and non-remitting EAE models, paralysis severity also correlated inversely with sparcl1:sparc transcript and SPARCL1:SPARC protein ratios directly in lumbar spinal cord tissue. In vitro, astrocyte production of both SPARCL1 and SPARC was regulated by T cell-derived cytokines, causing dynamic modulation of the SPARCL1:SPARC expression ratio. Taken together, these data support a model whereby proinflammatory cytokines inhibit SPARCL1 and/or augment SPARC expression by astrocytes in spinal gray matter that, in turn, cause either transient or sustained synaptic retraction from lumbar spinal motor neurons thereby regulating hind limb paralysis during EAE. Ongoing studies seek ways to alter this SPARCL1:SPARC expression ratio in favor of synapse reformation/maintenance and thus help to modulate neurologic deficits during times of inflammation. This could identify new astrocyte-targeted therapies for diseases such as multiple sclerosis.

No MeSH data available.


Related in: MedlinePlus