Critical role of p38 MAPK for regeneration of the sciatic nerve following crush injury in vivo

Journal of Neuroinflammation

Masato Ogata¹  Hiromi Oda⁴  Takahiko Fujikawa¹  David M Findlay⁵  Gerald J Atkins⁵  Masakazu Kogawa⁵  Masahito Matsumoto³  Naoki Kato² 

[1] Department of Biochemistry, Mie University School of Medicine, Mie, Japan;Department of Orthopaedic Surgery, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe City, Saitama, 350-8550, Japan;Division of Functional Genomics & Systems Medicine, Research Center of Genomic Medicine, Saitama Medical University, Saitama, Japan;Department of Orthopaedic Surgery, Saitama Medical University, Saitama, Japan;Discipline of Orthopaedics and Trauma, The University of Adelaide, Adelaide, Australia

关键词: In vivo;    Mutant mice;    IL-1β;    TNF-α;    Inflammatory cytokines;    Crush injury;    Nerve regeneration;    P38 MAPK;   

Others  :  1160085
DOI  :  10.1186/1742-2094-10-1

 received in 2012-07-29, accepted in 2012-12-10,  发布年份 2013

【 摘 要 】

Background

The physiological function of p38α, which is an isoform of p38 MAPK, has been investigated previously in several studies using pharmacological inhibitors. However, the results regarding whether p38α promotes or inhibits nerve regeneration in vivo have been controversial.

Methods

We generated novel p38α mutant mice (sem mice) with a point mutation in the region encoding the p38α substrate-docking-site, which serves as a limited loss-of-function model of p38α. In the present study, we utilized sem mice and wild-type littermates (wt mice) to investigate the physiological role of p38α in nerve regeneration following crush injuries.

Results

At four weeks after crush injury, the average axon diameter and the average axon area in sem mice were significantly smaller than those in wt mice. The average myelin sheath thickness in sem mice was reduced compared to wt mice, but no significant difference was observed in the G-ratio between the two groups. The sciatic functional index value demonstrated that functional nerve recovery in sem mice following crush injury was delayed, which is consistent with the histological findings. To investigate the underlying mechanisms of these findings, we examined inflammatory responses of the sciatic nerve by immunohistochemistry and western blotting. At an early phase following crush injury, sem mice showed remarkably lower expression of inflammatory cytokines, such as TNF-α and IL-1β, than wt mice. The expression of Caspase-3 and Tenascin-C were also lower in sem mice. Conversely, at a late phase of the response, sem mice showed considerably higher expression of TNF-α and of IL-1β with lower expression of S-100 than wt mice.

Conclusions

This is the first study of the physiological role of p38 MAPK in nerve regeneration that does not rely on the use of pharmacological inhibitors. Our results indicate that p38α insufficiency may cause an inflammatory disorder, resulting in a delay of histological and functional nerve recovery following crush injury. We conclude that p38 MAPK has an important physiological role in nerve regeneration and may be important for controlling both initiation of inflammation and recovery from nerve injury.

【 授权许可】

   
2013 Kato et al.; licensee BioMed Central Ltd.

【 图 表 】

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