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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

Some T cell-derived cytokines regulate astrocyte production of SPARC in vitro. (A) Astrocytes spontaneously secrete measurable amounts of SPARC into culture supernatants (n = 4 experimental replicates per time point). (B) TNF-α modestly induces astrocyte SPARC production (n = 3 experimental replicates per time point). (C) TNF-α suppresses the ratio of SPARCL1 to SPARC made by astrocytes over time, p < 0.0001 comparing ratio differences, p = 0.0002 comparing changes over time. (D) IL-10 augments the ratio of SPARCL1 to SPARC made by astrocytes over time, p < 0.0001 comparing ratio differences, p < 0.0001 comparing changes over time.
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Figure 7: Some T cell-derived cytokines regulate astrocyte production of SPARC in vitro. (A) Astrocytes spontaneously secrete measurable amounts of SPARC into culture supernatants (n = 4 experimental replicates per time point). (B) TNF-α modestly induces astrocyte SPARC production (n = 3 experimental replicates per time point). (C) TNF-α suppresses the ratio of SPARCL1 to SPARC made by astrocytes over time, p < 0.0001 comparing ratio differences, p = 0.0002 comparing changes over time. (D) IL-10 augments the ratio of SPARCL1 to SPARC made by astrocytes over time, p < 0.0001 comparing ratio differences, p < 0.0001 comparing changes over time.

Mentions: Spontaneous astrocyte production of SPARC was also robust (Figure 7A), although fewer of the cytokines tested modulated its release. TNF-α modestly increased SPARC production by these cells (Figure 7B), thereby shifting the SPARCL1:SPARC concentration ratio more in favor of synapse inhibition (Figure 7C). An opposite effect on this ratio was induced by IL-10 (Figure 7D), a change largely driven by its induction of SPARCL1 in astrocytes (Figure 6D). Both IFN-γ and IL-17 had no significant effect on SPARC release (data not shown). Nonetheless, these data show that in vitro production of this anti-synaptogenic molecule by astrocytes is also under some dynamic control by T cell-derived inflammatory mediators.


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)

Some T cell-derived cytokines regulate astrocyte production of SPARC in vitro. (A) Astrocytes spontaneously secrete measurable amounts of SPARC into culture supernatants (n = 4 experimental replicates per time point). (B) TNF-α modestly induces astrocyte SPARC production (n = 3 experimental replicates per time point). (C) TNF-α suppresses the ratio of SPARCL1 to SPARC made by astrocytes over time, p < 0.0001 comparing ratio differences, p = 0.0002 comparing changes over time. (D) IL-10 augments the ratio of SPARCL1 to SPARC made by astrocytes over time, p < 0.0001 comparing ratio differences, p < 0.0001 comparing changes over time.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 7: Some T cell-derived cytokines regulate astrocyte production of SPARC in vitro. (A) Astrocytes spontaneously secrete measurable amounts of SPARC into culture supernatants (n = 4 experimental replicates per time point). (B) TNF-α modestly induces astrocyte SPARC production (n = 3 experimental replicates per time point). (C) TNF-α suppresses the ratio of SPARCL1 to SPARC made by astrocytes over time, p < 0.0001 comparing ratio differences, p = 0.0002 comparing changes over time. (D) IL-10 augments the ratio of SPARCL1 to SPARC made by astrocytes over time, p < 0.0001 comparing ratio differences, p < 0.0001 comparing changes over time.
Mentions: Spontaneous astrocyte production of SPARC was also robust (Figure 7A), although fewer of the cytokines tested modulated its release. TNF-α modestly increased SPARC production by these cells (Figure 7B), thereby shifting the SPARCL1:SPARC concentration ratio more in favor of synapse inhibition (Figure 7C). An opposite effect on this ratio was induced by IL-10 (Figure 7D), a change largely driven by its induction of SPARCL1 in astrocytes (Figure 6D). Both IFN-γ and IL-17 had no significant effect on SPARC release (data not shown). Nonetheless, these data show that in vitro production of this anti-synaptogenic molecule by astrocytes is also under some dynamic control by T cell-derived inflammatory mediators.

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