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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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Administration of recombinant IL-1β or absence of IL-1β alters numbers of corticospinal tract fibers. (A), (B) Representative micrographs of the area of the spinal cord between the corticospinal tract (CST) end and 5 mm caudal to the lesion center (LC). Higher magnification panels highlight the area between the end of the CST and the LC and one selected area (recombinant IL-1β (rIL-1β)) to four selected areas (IL-1βKO) caudal to the LC, where diaminobenzidine-positive fibers could be detected. Arrows indicate CST fibers caudal to the LC.
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Figure 5: Administration of recombinant IL-1β or absence of IL-1β alters numbers of corticospinal tract fibers. (A), (B) Representative micrographs of the area of the spinal cord between the corticospinal tract (CST) end and 5 mm caudal to the lesion center (LC). Higher magnification panels highlight the area between the end of the CST and the LC and one selected area (recombinant IL-1β (rIL-1β)) to four selected areas (IL-1βKO) caudal to the LC, where diaminobenzidine-positive fibers could be detected. Arrows indicate CST fibers caudal to the LC.

Mentions: Conversely, the absence of IL-1β in IL-1βKO mice significantly promoted functional recovery after SCI compared with WT mice (Figure4A), as indicated by a difference of 1 point of the BMS between experimental groups (from about 6.8 for the WT mice to about 7.8 for IL-1βKO mice). Analysis of the stepping subscore of the BMS showed a negative trend after administration of rIL-1β that did not reach significance, while in the paw positioning subscore a statistically significant difference was found (Figure2B). On the contrary, IL-1β deficiency led to an almost identical stepping score but significantly improved the paw positioning score (Figure4B), indicating that this parameter (degree of rotation of the hind paws) is of particular relevance to the difference in the functional recovery not only between PBS and rIL-1β-treated mice, but also between knockout and WT mice. In the next step, we analyzed the number of BDA-traced CST fibers as a marker for axonal plasticity induced by absence or increased levels of IL-1β at defined distances from the lesion center (Figures5 and6). Treatment of the injured mice with rIL-1β significantly reduced the number of labeled axons 5 mm distal to the lesion center compared with PBS-treated mice (Figure5, upper panels and Figure6A). In contrast, IL-1β absence in IL-1βKO mice led to a significant increase of BDA-positive fibers in the area 5 mm distal to the lesion and to the development of complex branches (Figure5, lower panels and Figure6B). Quantification of BDA-positive fibers, which were normalized (on spinal cord cross-sections of the spinal cord) to the total number of labeled CST fibers cranial to the lesion center, showed that the percentage of fibers present 5 mm distal to the lesion was reduced about 15-fold in rIL-1β-treated mice compared with PBS-treated mice (Figure6A) and was increased about fivefold in IL-1βKO mice compared with WT (Figure6B). So far, these data provided strong evidence for a neurodegenerative effect of rIL-1β applied on the site of the lesion after spinal cord injury, while genetic depletion of IL-1β resulted in a significantly improved recovery after injury and had a strong beneficial effect on plasticity (including local sprouting) of CST fibers. GFAP immunoreactivity did not significantly differ in mice with or without rIL-1β administration (Figure7A, C upper panels) and was also not significantly different between WT and IL-1βKO mice when analyzing the entire dorso-ventral axis of the spinal cord (Figure7B, 7C lower panels). In contrast, GFAP distribution was highly reduced (>60%) in IL-1βKO mice when focusing the analysis on the white matter (Figure7D), as shown in a representative photomicrograph (Figure7E) demonstrating a substantially reduced astrogliosis after SCI in the absence of systemic IL-1β.


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)

Administration of recombinant IL-1β or absence of IL-1β alters numbers of corticospinal tract fibers. (A), (B) Representative micrographs of the area of the spinal cord between the corticospinal tract (CST) end and 5 mm caudal to the lesion center (LC). Higher magnification panels highlight the area between the end of the CST and the LC and one selected area (recombinant IL-1β (rIL-1β)) to four selected areas (IL-1βKO) caudal to the LC, where diaminobenzidine-positive fibers could be detected. Arrows indicate CST fibers caudal to the LC.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Administration of recombinant IL-1β or absence of IL-1β alters numbers of corticospinal tract fibers. (A), (B) Representative micrographs of the area of the spinal cord between the corticospinal tract (CST) end and 5 mm caudal to the lesion center (LC). Higher magnification panels highlight the area between the end of the CST and the LC and one selected area (recombinant IL-1β (rIL-1β)) to four selected areas (IL-1βKO) caudal to the LC, where diaminobenzidine-positive fibers could be detected. Arrows indicate CST fibers caudal to the LC.
Mentions: Conversely, the absence of IL-1β in IL-1βKO mice significantly promoted functional recovery after SCI compared with WT mice (Figure4A), as indicated by a difference of 1 point of the BMS between experimental groups (from about 6.8 for the WT mice to about 7.8 for IL-1βKO mice). Analysis of the stepping subscore of the BMS showed a negative trend after administration of rIL-1β that did not reach significance, while in the paw positioning subscore a statistically significant difference was found (Figure2B). On the contrary, IL-1β deficiency led to an almost identical stepping score but significantly improved the paw positioning score (Figure4B), indicating that this parameter (degree of rotation of the hind paws) is of particular relevance to the difference in the functional recovery not only between PBS and rIL-1β-treated mice, but also between knockout and WT mice. In the next step, we analyzed the number of BDA-traced CST fibers as a marker for axonal plasticity induced by absence or increased levels of IL-1β at defined distances from the lesion center (Figures5 and6). Treatment of the injured mice with rIL-1β significantly reduced the number of labeled axons 5 mm distal to the lesion center compared with PBS-treated mice (Figure5, upper panels and Figure6A). In contrast, IL-1β absence in IL-1βKO mice led to a significant increase of BDA-positive fibers in the area 5 mm distal to the lesion and to the development of complex branches (Figure5, lower panels and Figure6B). Quantification of BDA-positive fibers, which were normalized (on spinal cord cross-sections of the spinal cord) to the total number of labeled CST fibers cranial to the lesion center, showed that the percentage of fibers present 5 mm distal to the lesion was reduced about 15-fold in rIL-1β-treated mice compared with PBS-treated mice (Figure6A) and was increased about fivefold in IL-1βKO mice compared with WT (Figure6B). So far, these data provided strong evidence for a neurodegenerative effect of rIL-1β applied on the site of the lesion after spinal cord injury, while genetic depletion of IL-1β resulted in a significantly improved recovery after injury and had a strong beneficial effect on plasticity (including local sprouting) of CST fibers. GFAP immunoreactivity did not significantly differ in mice with or without rIL-1β administration (Figure7A, C upper panels) and was also not significantly different between WT and IL-1βKO mice when analyzing the entire dorso-ventral axis of the spinal cord (Figure7B, 7C lower panels). In contrast, GFAP distribution was highly reduced (>60%) in IL-1βKO mice when focusing the analysis on the white matter (Figure7D), as shown in a representative photomicrograph (Figure7E) demonstrating a substantially reduced astrogliosis after SCI in the absence of systemic IL-1β.

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