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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

Astrocytes are activated in both gray and white matter of the lumbar ventral spinal cord during relapsing EAE. (A) The clinical course of relapsing EAE induced by active PLP peptide immunization of SJL mice shows near complete resolution of paralysis over only a few days (n = 20). (B) Normalized spinal cord GFAP levels at defined stages of relapsing EAE shows evidence of astrocyte activation at disease onset (n = 5 samples per disease stage). (C) Representative immunohistochemical staining for GFAP expression in naïve SJL spinal cord shows expression in quiescent-appearing cells that predominate in white matter. Insert shows modest signal in ventral gray matter. (D) Representative GFAP staining of SJL spinal cord at peak EAE shows increased signal in both white and gray matter. Insert shows numerous activated GFAP+ astrocytes in ventral gray matter. *p < 0.05 compared to preclinical levels, Bar = 100 μm.
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Figure 1: Astrocytes are activated in both gray and white matter of the lumbar ventral spinal cord during relapsing EAE. (A) The clinical course of relapsing EAE induced by active PLP peptide immunization of SJL mice shows near complete resolution of paralysis over only a few days (n = 20). (B) Normalized spinal cord GFAP levels at defined stages of relapsing EAE shows evidence of astrocyte activation at disease onset (n = 5 samples per disease stage). (C) Representative immunohistochemical staining for GFAP expression in naïve SJL spinal cord shows expression in quiescent-appearing cells that predominate in white matter. Insert shows modest signal in ventral gray matter. (D) Representative GFAP staining of SJL spinal cord at peak EAE shows increased signal in both white and gray matter. Insert shows numerous activated GFAP+ astrocytes in ventral gray matter. *p < 0.05 compared to preclinical levels, Bar = 100 μm.

Mentions: Immunization of female SJL mice with the myelin peptide, PLP139−151, produced a relapsing form of EAE where the initial hind limb paralysis remitted from peak disease severity over just a few days (Figure 1A). In this disease setting, we found that astrocyte activation in the lumbar spinal cord, as assessed by Western blot expression of the intermediate filament protein, GFAP, preceded the onset of symptoms, reached a peak as hind limb paralysis emerged, and declined with clinical remission (Figure 1B). While inflammatory cell infiltration predominated in the surrounding white matter tracts of mice with relapsing EAE (data not shown), GFAP expression changes were identified by immunohistochemistry in both gray and white matter regions of the lumbar spinal cord at peak disease (Figure 1D) compared to naïve controls (Figure 1C). These dynamic astroglial responses in spinal gray matter raised the possibility that interactions with adjacent neurons might also change over the course of relapse and remission.


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)

Astrocytes are activated in both gray and white matter of the lumbar ventral spinal cord during relapsing EAE. (A) The clinical course of relapsing EAE induced by active PLP peptide immunization of SJL mice shows near complete resolution of paralysis over only a few days (n = 20). (B) Normalized spinal cord GFAP levels at defined stages of relapsing EAE shows evidence of astrocyte activation at disease onset (n = 5 samples per disease stage). (C) Representative immunohistochemical staining for GFAP expression in naïve SJL spinal cord shows expression in quiescent-appearing cells that predominate in white matter. Insert shows modest signal in ventral gray matter. (D) Representative GFAP staining of SJL spinal cord at peak EAE shows increased signal in both white and gray matter. Insert shows numerous activated GFAP+ astrocytes in ventral gray matter. *p < 0.05 compared to preclinical levels, Bar = 100 μm.
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Related In: Results  -  Collection

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Show All Figures
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Figure 1: Astrocytes are activated in both gray and white matter of the lumbar ventral spinal cord during relapsing EAE. (A) The clinical course of relapsing EAE induced by active PLP peptide immunization of SJL mice shows near complete resolution of paralysis over only a few days (n = 20). (B) Normalized spinal cord GFAP levels at defined stages of relapsing EAE shows evidence of astrocyte activation at disease onset (n = 5 samples per disease stage). (C) Representative immunohistochemical staining for GFAP expression in naïve SJL spinal cord shows expression in quiescent-appearing cells that predominate in white matter. Insert shows modest signal in ventral gray matter. (D) Representative GFAP staining of SJL spinal cord at peak EAE shows increased signal in both white and gray matter. Insert shows numerous activated GFAP+ astrocytes in ventral gray matter. *p < 0.05 compared to preclinical levels, Bar = 100 μm.
Mentions: Immunization of female SJL mice with the myelin peptide, PLP139−151, produced a relapsing form of EAE where the initial hind limb paralysis remitted from peak disease severity over just a few days (Figure 1A). In this disease setting, we found that astrocyte activation in the lumbar spinal cord, as assessed by Western blot expression of the intermediate filament protein, GFAP, preceded the onset of symptoms, reached a peak as hind limb paralysis emerged, and declined with clinical remission (Figure 1B). While inflammatory cell infiltration predominated in the surrounding white matter tracts of mice with relapsing EAE (data not shown), GFAP expression changes were identified by immunohistochemistry in both gray and white matter regions of the lumbar spinal cord at peak disease (Figure 1D) compared to naïve controls (Figure 1C). These dynamic astroglial responses in spinal gray matter raised the possibility that interactions with adjacent neurons might also change over the course of relapse and remission.

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