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The Journal of Neuroscience, November 14, 2007, 27(46):12565-12576; doi:10.1523/JNEUROSCI.3027-07.2007

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Cellular/Molecular
Toll-Like Receptor Signaling Is Critical for Wallerian Degeneration and Functional Recovery after Peripheral Nerve Injury

Audrey Boivin, Isabelle Pineau, Benoit Barrette, Mohammed Filali, Nicolas Vallières, Serge Rivest, and Steve Lacroix

Laboratory of Molecular Endocrinology, CHUL Research Center, and Department of Anatomy and Physiology, Faculty of Medicine, Laval University, Ste-Foy, Québec, Canada G1V 4G2

Correspondence should be addressed to Dr. Steve Lacroix, CHUL Research Center and Laval University, 2705 Laurier Boulevard, Ste-Foy, Québec, Canada G1V 4G2. Email: Steve.Lacroix{at}crchul.ulaval.ca

Toll-like receptors (TLRs) bind specific components conserved among microorganisms as well as endogenous ligands produced by necrotic cells, injured axons, and the extracellular matrix. Here, we investigated whether TLRs are involved in regulating the immune response, Wallerian degeneration (WD), and nerve regeneration after sciatic nerve lesion. Early expression of interleukin-1ß and monocyte chemoattractant protein-1 was compromised in the sciatic nerve distal stump of mice deficient in TLR signaling. In addition, significantly fewer macrophages were recruited and/or activated in the sciatic nerve distal stump of TLR2-, TLR4-, and MyD88-deficient mice compared with wild-type littermates, whereas WD, axonal regeneration, and recovery of locomotor function were impaired. In contrast, animals that received a single microinjection of TLR2 and TLR4 ligands at the site of sciatic nerve lesion had faster clearance of the degenerating myelin and recovered earlier than saline-injected control rats. Finally, rats that had altered innate immune response through dexamethasone treatment exhibited three times more myelin debris in their sciatic nerve distal stump and a significant delay in recovery of locomotor function. Our results provide strong evidence that TLR signaling plays a critical role in orchestrating the innate immune response leading to efficient and rapid clearance of inhibitory myelin debris and nerve regeneration.

Key words: sciatic nerve; macrophages; lipopolysaccharide; zymosan; myelin inhibitors; axonal regeneration

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Received July 3, 2007; revised Sept. 21, 2007; accepted Oct. 1, 2007.

Correspondence should be addressed to Dr. Steve Lacroix, CHUL Research Center and Laval University, 2705 Laurier Boulevard, Ste-Foy, Québec, Canada G1V 4G2. Email: Steve.Lacroix{at}crchul.ulaval.ca

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				D. B. Parkinson, A. Bhaskaran, P. Arthur-Farraj, L. A. Noon, A. Woodhoo, A. C. Lloyd, M. L. Feltri, L. Wrabetz, A. Behrens, R. Mirsky, et al. c-Jun is a negative regulator of myelination J. Cell Biol., May 19, 2008; 181(4): 625 - 637. [Abstract] [Full Text] [PDF]

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