Functional recovery after peripheral nerve injury is dependent on the pro-inflammatory cytokines IL-1β and TNF

Implications for neuropathic pain

Sylvain Nadeau, Mohammed Filali, Ji Zhang, Bradley J. Kerr, Serge Rivest, Denis Soulet, Yoichiro Iwakura, Juan Pablo P de Rivero Vaccari, Robert Keane, Steve Lacroix

Research output: Contribution to journalArticle

154 Citations (Scopus)

Abstract

IL-1β and TNF are potential targets in the management of neuropathic pain after injury. However, the importance of the IL-1 and TNF systems for peripheral nerve regeneration and the mechanisms by which these cytokines mediate effects are to be fully elucidated. Here, we demonstrate thatmRNAand protein levels of IL-1β and TNF are rapidly upregulated in the injured mouse sciatic nerve. Mice lacking both IL-1β and TNF, or both IL-1 type 1 receptor (IL-1R1) and TNF type 1 receptor (TNFR1), showed reduced nociceptive sensitivity (mechanical allodynia) compared with wild-type littermates after injury. Microinjecting recombinant IL-1β or TNF at the site of sciatic nerve injury in IL-1β- and TNF-knock-out mice restored mechanical pain thresholds back to levels observed in injured wild-type mice. Importantly, recovery of sciatic nerve function was impaired in IL-1β-, TNF-, and IL-1β/TNF-knock-out mice. Notably, the infiltration of neutrophils was almost completely prevented in the sciatic nerve distal stump of mice lacking both IL-1R1 and TNFR1. Systemic treatment of mice with an anti-Ly6G antibody to deplete neutrophils, cells that play an essential role in the genesis of neuropathic pain, did not affect recovery of neurological function and peripheral axon regeneration. Together, these results suggest that targeting specific IL-1β/ TNF-dependent responses, such as neutrophil infiltration, is a better therapeutic strategy for treatment of neuropathic pain after peripheral nerve injury than complete blockage of cytokine production.

Original languageEnglish
Pages (from-to)12533-12542
Number of pages10
JournalJournal of Neuroscience
Volume31
Issue number35
DOIs
StatePublished - Aug 31 2011

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Peripheral Nerve Injuries
Neuralgia
Interleukin-1
Cytokines
Sciatic Nerve
Receptors, Tumor Necrosis Factor, Type I
Neutrophil Infiltration
Knockout Mice
Wounds and Injuries
Nerve Regeneration
Pain Threshold
Interleukin-1 Receptors
Tumor Necrosis Factor Receptors
Hyperalgesia
Recovery of Function
Peripheral Nerves
Axons
Regeneration
Anti-Idiotypic Antibodies
Neutrophils

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Functional recovery after peripheral nerve injury is dependent on the pro-inflammatory cytokines IL-1β and TNF : Implications for neuropathic pain. / Nadeau, Sylvain; Filali, Mohammed; Zhang, Ji; Kerr, Bradley J.; Rivest, Serge; Soulet, Denis; Iwakura, Yoichiro; de Rivero Vaccari, Juan Pablo P; Keane, Robert; Lacroix, Steve.

In: Journal of Neuroscience, Vol. 31, No. 35, 31.08.2011, p. 12533-12542.

Research output: Contribution to journalArticle

Nadeau, Sylvain ; Filali, Mohammed ; Zhang, Ji ; Kerr, Bradley J. ; Rivest, Serge ; Soulet, Denis ; Iwakura, Yoichiro ; de Rivero Vaccari, Juan Pablo P ; Keane, Robert ; Lacroix, Steve. / Functional recovery after peripheral nerve injury is dependent on the pro-inflammatory cytokines IL-1β and TNF : Implications for neuropathic pain. In: Journal of Neuroscience. 2011 ; Vol. 31, No. 35. pp. 12533-12542.
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