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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 both sparcl1 and sparc transcripts and SPARCL1 and SPARC proteins changes in lumbar spinal cord tissue over the course of relapsing EAE in SJL mice. (A) Relative sparcl1 mRNA expression fluxes over the course of relapsing EAE (n = 5 mice per disease stage). (B) Relative sparc mRNA expression also changes over the course of relapsing EAE (n = 5 mice per disease stage). (C) The calculated sparcl1 to sparc mRNA expression ratio shifts in favor of synapse inhibition at peak disease. (D) The same change in the SPARCL1 to SPARC protein concentration ratios is seen over the course of relapsing EAE (n = 5 mice per disease stage). *p < 0.05 compared to levels found in naïve spinal cord.
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Figure 4: Expression of both sparcl1 and sparc transcripts and SPARCL1 and SPARC proteins changes in lumbar spinal cord tissue over the course of relapsing EAE in SJL mice. (A) Relative sparcl1 mRNA expression fluxes over the course of relapsing EAE (n = 5 mice per disease stage). (B) Relative sparc mRNA expression also changes over the course of relapsing EAE (n = 5 mice per disease stage). (C) The calculated sparcl1 to sparc mRNA expression ratio shifts in favor of synapse inhibition at peak disease. (D) The same change in the SPARCL1 to SPARC protein concentration ratios is seen over the course of relapsing EAE (n = 5 mice per disease stage). *p < 0.05 compared to levels found in naïve spinal cord.

Mentions: The matricellular proteins, SPARC and SPARCL1, are produced by astrocytes and regulate excitatory synaptogenesis in vitro and in the developing CNS in vivo (Kucukdereli et al., 2011). While SPARCL1 directly promotes excitatory synapse formation, SPARC specifically antagonizes its synaptogenic activity (Kucukdereli et al., 2011). Both proteins are expressed in the adult CNS (Lloyd-Burton and Roskams, 2012), although their direct effects over existing excitatory synapses has not been reported. Given dynamic changes to both astrocytes and synapses in the lumbar gray matter of mice with relapsing EAE (Figures 1–3), we investigated whether local tissue expression of either SPARCL1 or SPARC changed over the course of this disease. Real-time PCR analysis showed that sparcl1 transcript levels declined in lumbar spinal cord with the onset of CNS inflammation, were further suppressed at peak disease, but then increased during remission in SJL mice with EAE (Figure 4A). Transcript levels of its known inhibitor, sparc, also declined during the preclinical stage of disease but increased thereafter (Figure 4B). When sparcl1:sparc transcript ratios were calculated, a dramatic, but transient, shift favoring synapse inhibition was seen at peak disease (Figure 4C). A similar pattern in the SPARCL1:SPARC protein expression ratios was observed in spinal cord tissues over the course of disease when each protein was measured by ELISA (Figure 4D).


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 both sparcl1 and sparc transcripts and SPARCL1 and SPARC proteins changes in lumbar spinal cord tissue over the course of relapsing EAE in SJL mice. (A) Relative sparcl1 mRNA expression fluxes over the course of relapsing EAE (n = 5 mice per disease stage). (B) Relative sparc mRNA expression also changes over the course of relapsing EAE (n = 5 mice per disease stage). (C) The calculated sparcl1 to sparc mRNA expression ratio shifts in favor of synapse inhibition at peak disease. (D) The same change in the SPARCL1 to SPARC protein concentration ratios is seen over the course of relapsing EAE (n = 5 mice per disease stage). *p < 0.05 compared to levels found in naïve spinal cord.
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Related In: Results  -  Collection

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

Figure 4: Expression of both sparcl1 and sparc transcripts and SPARCL1 and SPARC proteins changes in lumbar spinal cord tissue over the course of relapsing EAE in SJL mice. (A) Relative sparcl1 mRNA expression fluxes over the course of relapsing EAE (n = 5 mice per disease stage). (B) Relative sparc mRNA expression also changes over the course of relapsing EAE (n = 5 mice per disease stage). (C) The calculated sparcl1 to sparc mRNA expression ratio shifts in favor of synapse inhibition at peak disease. (D) The same change in the SPARCL1 to SPARC protein concentration ratios is seen over the course of relapsing EAE (n = 5 mice per disease stage). *p < 0.05 compared to levels found in naïve spinal cord.
Mentions: The matricellular proteins, SPARC and SPARCL1, are produced by astrocytes and regulate excitatory synaptogenesis in vitro and in the developing CNS in vivo (Kucukdereli et al., 2011). While SPARCL1 directly promotes excitatory synapse formation, SPARC specifically antagonizes its synaptogenic activity (Kucukdereli et al., 2011). Both proteins are expressed in the adult CNS (Lloyd-Burton and Roskams, 2012), although their direct effects over existing excitatory synapses has not been reported. Given dynamic changes to both astrocytes and synapses in the lumbar gray matter of mice with relapsing EAE (Figures 1–3), we investigated whether local tissue expression of either SPARCL1 or SPARC changed over the course of this disease. Real-time PCR analysis showed that sparcl1 transcript levels declined in lumbar spinal cord with the onset of CNS inflammation, were further suppressed at peak disease, but then increased during remission in SJL mice with EAE (Figure 4A). Transcript levels of its known inhibitor, sparc, also declined during the preclinical stage of disease but increased thereafter (Figure 4B). When sparcl1:sparc transcript ratios were calculated, a dramatic, but transient, shift favoring synapse inhibition was seen at peak disease (Figure 4C). A similar pattern in the SPARCL1:SPARC protein expression ratios was observed in spinal cord tissues over the course of disease when each protein was measured by ELISA (Figure 4D).

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