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Absence of IL-1β positively affects neurological outcome, lesion development and axonal plasticity after spinal cord injury.

Boato F, Rosenberger K, Nelissen S, Geboes L, Peters EM, Nitsch R, Hendrix S - J Neuroinflammation (2013)

Bottom Line: In contrast to our hypothesis, the histological analysis revealed a significantly increased lesion width and a reduced number of corticospinal tract fibers caudal to the lesion center after local application of recombinant IL-1β.Histological analysis revealed a smaller lesion size, reduced lesion width and greatly decreased astrogliosis in the white matter, while the number of corticospinal tract fibers increased significantly 5 mm caudal to the lesion in IL-1βKO mice relative to controls.Our study for the first time characterizes the detrimental effects of IL-1β not only on lesion development (in terms of size and glia activation), but also on the plasticity of central nervous system axons after injury.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Morphology & BIOMED Institute, Campus Diepenbeek, Hasselt University, Agoralaan Gebouw C, Diepenbeek, BE 3590, Belgium.

ABSTRACT
Precise crosstalk between the nervous and immune systems is important for neuroprotection and axon plasticity after injury. Recently, we demonstrated that IL-1β acts as a potent inducer of neurite outgrowth from organotypic brain slices in vitro, suggesting a potential function of IL-1β in axonal plasticity. Here, we have investigated the effects of IL-1β on axon plasticity during glial scar formation and on functional recovery in a mouse model of spinal cord compression injury (SCI). We used an IL-1β deficiency model (IL-1βKO mice) and administered recombinant IL-1β. In contrast to our hypothesis, the histological analysis revealed a significantly increased lesion width and a reduced number of corticospinal tract fibers caudal to the lesion center after local application of recombinant IL-1β. Consistently, the treatment significantly worsened the neurological outcome after SCI in mice compared with PBS controls. In contrast, the absence of IL-1β in IL-1βKO mice significantly improved recovery from SCI compared with wildtype mice. Histological analysis revealed a smaller lesion size, reduced lesion width and greatly decreased astrogliosis in the white matter, while the number of corticospinal tract fibers increased significantly 5 mm caudal to the lesion in IL-1βKO mice relative to controls. Our study for the first time characterizes the detrimental effects of IL-1β not only on lesion development (in terms of size and glia activation), but also on the plasticity of central nervous system axons after injury.

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Application of recombinant IL-1β impairs neurological outcome after spinal cord compression injury. (A) Locomotion analysis using the Basso Mouse Scale (BMS) showed significant worsening of neurological outcome after spinal cord compression injury (SCI) and local administration of recombinant IL-1β (rIL-1β) in Gelfoam directly after SCI. The rIL-1β-treated mice scored more than 1 point of the BMS less than control mice (scoring respectively 4.5 and 6), most probably reflecting lack of coordination and consistent plantar stepping in the treated mice. (B) The paw positioning subscore differed significantly between the two groups, while the stepping subscore did not. *P <0.05, two-way analysis of variance.
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Figure 2: Application of recombinant IL-1β impairs neurological outcome after spinal cord compression injury. (A) Locomotion analysis using the Basso Mouse Scale (BMS) showed significant worsening of neurological outcome after spinal cord compression injury (SCI) and local administration of recombinant IL-1β (rIL-1β) in Gelfoam directly after SCI. The rIL-1β-treated mice scored more than 1 point of the BMS less than control mice (scoring respectively 4.5 and 6), most probably reflecting lack of coordination and consistent plantar stepping in the treated mice. (B) The paw positioning subscore differed significantly between the two groups, while the stepping subscore did not. *P <0.05, two-way analysis of variance.

Mentions: In a first experimental approach we applied a high dosage of rIL-1β to mice that underwent spinal cord injury. To our knowledge this is the first study to investigate the in vivo effect of rIL-1β on axonal plasticity in the CNS, so the choice of the rIL-1β in vivo dosage was based on in vitro results from our group. Perilesional administration of 20 μg rIL-1β in Gelfoam immediately after SCI resulted in 100% mortality, with all mice (n = 7) dying within the first 4 days after the operation (Figure1). We refrained from repeating the experiment to perform necropsies to diagnose the cause of death for obvious ethical reasons. Based on these results, we used a drastically reduced amount of cytokine (1 μg in 5 μl PBS), which substantially reduced the mortality (only one out of eight operated mice died 3 days after injury). The application of 1 μg rIL-1β significantly impaired functional performance compared with mice treated with PBS alone (Figure2A). At the end of the investigation period (14 days after injury) the two experimental groups varied by more than one point on the BMS (from about 4.5 for rIL-1β-treated mice to 6 for PBS-treated mice), mainly reflecting a substantial difference in coordination and consistency of plantar stepping during walking. To rule out the possibility that the effect of rIL-1β-mediated worsened neurological outcome after SCI was due to a systemic effect of the cytokine, we applied 1 μg IL-1β systemically (intraperitoneal injection) after lesion (Figure3). Under these conditions the treated mice showed a significant worsening of neurological outcome from day 2 to day 5 of the observation period, scoring more than 2 points of the BMS less than control mice in the first 2 days. They progressively improved at a higher rate if compared with mice treated only with PBS, and by day 7 of the scoring the significant difference between the two groups was lost.


Absence of IL-1β positively affects neurological outcome, lesion development and axonal plasticity after spinal cord injury.

Boato F, Rosenberger K, Nelissen S, Geboes L, Peters EM, Nitsch R, Hendrix S - J Neuroinflammation (2013)

Application of recombinant IL-1β impairs neurological outcome after spinal cord compression injury. (A) Locomotion analysis using the Basso Mouse Scale (BMS) showed significant worsening of neurological outcome after spinal cord compression injury (SCI) and local administration of recombinant IL-1β (rIL-1β) in Gelfoam directly after SCI. The rIL-1β-treated mice scored more than 1 point of the BMS less than control mice (scoring respectively 4.5 and 6), most probably reflecting lack of coordination and consistent plantar stepping in the treated mice. (B) The paw positioning subscore differed significantly between the two groups, while the stepping subscore did not. *P <0.05, two-way analysis of variance.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3585738&req=5

Figure 2: Application of recombinant IL-1β impairs neurological outcome after spinal cord compression injury. (A) Locomotion analysis using the Basso Mouse Scale (BMS) showed significant worsening of neurological outcome after spinal cord compression injury (SCI) and local administration of recombinant IL-1β (rIL-1β) in Gelfoam directly after SCI. The rIL-1β-treated mice scored more than 1 point of the BMS less than control mice (scoring respectively 4.5 and 6), most probably reflecting lack of coordination and consistent plantar stepping in the treated mice. (B) The paw positioning subscore differed significantly between the two groups, while the stepping subscore did not. *P <0.05, two-way analysis of variance.
Mentions: In a first experimental approach we applied a high dosage of rIL-1β to mice that underwent spinal cord injury. To our knowledge this is the first study to investigate the in vivo effect of rIL-1β on axonal plasticity in the CNS, so the choice of the rIL-1β in vivo dosage was based on in vitro results from our group. Perilesional administration of 20 μg rIL-1β in Gelfoam immediately after SCI resulted in 100% mortality, with all mice (n = 7) dying within the first 4 days after the operation (Figure1). We refrained from repeating the experiment to perform necropsies to diagnose the cause of death for obvious ethical reasons. Based on these results, we used a drastically reduced amount of cytokine (1 μg in 5 μl PBS), which substantially reduced the mortality (only one out of eight operated mice died 3 days after injury). The application of 1 μg rIL-1β significantly impaired functional performance compared with mice treated with PBS alone (Figure2A). At the end of the investigation period (14 days after injury) the two experimental groups varied by more than one point on the BMS (from about 4.5 for rIL-1β-treated mice to 6 for PBS-treated mice), mainly reflecting a substantial difference in coordination and consistency of plantar stepping during walking. To rule out the possibility that the effect of rIL-1β-mediated worsened neurological outcome after SCI was due to a systemic effect of the cytokine, we applied 1 μg IL-1β systemically (intraperitoneal injection) after lesion (Figure3). Under these conditions the treated mice showed a significant worsening of neurological outcome from day 2 to day 5 of the observation period, scoring more than 2 points of the BMS less than control mice in the first 2 days. They progressively improved at a higher rate if compared with mice treated only with PBS, and by day 7 of the scoring the significant difference between the two groups was lost.

Bottom Line: In contrast to our hypothesis, the histological analysis revealed a significantly increased lesion width and a reduced number of corticospinal tract fibers caudal to the lesion center after local application of recombinant IL-1β.Histological analysis revealed a smaller lesion size, reduced lesion width and greatly decreased astrogliosis in the white matter, while the number of corticospinal tract fibers increased significantly 5 mm caudal to the lesion in IL-1βKO mice relative to controls.Our study for the first time characterizes the detrimental effects of IL-1β not only on lesion development (in terms of size and glia activation), but also on the plasticity of central nervous system axons after injury.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Morphology & BIOMED Institute, Campus Diepenbeek, Hasselt University, Agoralaan Gebouw C, Diepenbeek, BE 3590, Belgium.

ABSTRACT
Precise crosstalk between the nervous and immune systems is important for neuroprotection and axon plasticity after injury. Recently, we demonstrated that IL-1β acts as a potent inducer of neurite outgrowth from organotypic brain slices in vitro, suggesting a potential function of IL-1β in axonal plasticity. Here, we have investigated the effects of IL-1β on axon plasticity during glial scar formation and on functional recovery in a mouse model of spinal cord compression injury (SCI). We used an IL-1β deficiency model (IL-1βKO mice) and administered recombinant IL-1β. In contrast to our hypothesis, the histological analysis revealed a significantly increased lesion width and a reduced number of corticospinal tract fibers caudal to the lesion center after local application of recombinant IL-1β. Consistently, the treatment significantly worsened the neurological outcome after SCI in mice compared with PBS controls. In contrast, the absence of IL-1β in IL-1βKO mice significantly improved recovery from SCI compared with wildtype mice. Histological analysis revealed a smaller lesion size, reduced lesion width and greatly decreased astrogliosis in the white matter, while the number of corticospinal tract fibers increased significantly 5 mm caudal to the lesion in IL-1βKO mice relative to controls. Our study for the first time characterizes the detrimental effects of IL-1β not only on lesion development (in terms of size and glia activation), but also on the plasticity of central nervous system axons after injury.

Show MeSH
Related in: MedlinePlus