The Extent of Cytokine Induction in Peripheral Nerve Lesions Depends on the Mode of Injury and NMDA Receptor Signaling

Background: Nerve injury leads to a degeneration of distal nerve segments, a process named Wallerian degeneration (WD). In the peripheral nervous system (PNS), WD is followed by prompt nerve regeneration facilitated by axonal sprouting from the proximal stumps of injured nerve fibers. Infiltration by inflammatory cells and local induction of chemokines and cytokines play an essential role in this process. Objectives: In the present study we asked whether cytokine gene induction is dependent on the mode of nerve injury and if it involves NMDA signaling. Methods: Interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, IL-10 and monocyte chemoattractant protein (MCP)-1 induction in the total of 185 mice were assessed in degenerating nerve stumps by quantitative reverse transcriptase polymerase chain reaction and compared between sciatic nerve crush and chronic constriction injury (CCI). Results: Cytokine mRNA levels showed an early and steep increase at day 1 after nerve crush (p<0.001 compared to controls) which was still significant at day 3, and returned to control levels at day 7 and later. CCI led to a similar early gene induction of IL-1beta and TNF-alpha peaking at day 1 which was of a higher magnitude and showed a more sustained time course lasting up to day 28 after surgery. In both lesion paradigms, MCP-1 induction peaked at day 1 (p<0.001 compared to controls), significantly decreased at day 3, and normalized thereafter. The anti-inflammatory cytokine IL-10 showed a different gene expression profile with an early and strong induction at day 1, but maximum levels at the third postoperative day after CCI. In general, transcripts of all cytokines reached 2–5-fold higher levels after CCI, and remained elevated for a longer period of time compared to crush injury. NMDA receptor blockade significantly reduced cytokine expression after CCI on the mRNA and protein level. In dorsal root ganglia, only IL-10 mRNA levels were modified after nerve injury (p<0.05 compared to controls). Conclusion: Our study indicates that the mode of nerve injury influences the extent of cytokine expression, and identifies NMDA-mediated signaling as one mechanism of cytokine induction in peripheral nerves.