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

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

doi:10.1523/jneurosci.3027-07.2007

Cited by 218 publications

(227 citation statements)

References 78 publications

(113 reference statements)

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“…While the selected myelination‐associated genes ( Mpz, Mbp, Prx, Mag, Pmp22 ) were consistently higher expressed in younger mice, investigated genes involved in Schwann cell dedifferentiation ( Shh, Jun, Gdnf ) were more abundant in intact nerves of old mice. Old nerves also showed higher expression of macrophage markers Iba‐1 and Toll‐like receptors 2 and 4 ( Tlr2, Tlr4 ); both said to be highly involved in Wallerian degeneration (Boivin et al, 2007). These data confirmed our enrichment analysis that inflammaging accompanies reduced myelination in intact sciatic nerves of old mice.…”

Section: Resultsmentioning

confidence: 99%

Inflammaging impairs peripheral nerve maintenance and regeneration

et al. 2018

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The regenerative capacity of peripheral nerves declines during aging, contributing to the development of neuropathies, limiting organism function. Changes in Schwann cells prompt failures in instructing maintenance and regeneration of aging nerves; molecular mechanisms of which have yet to be delineated. Here, we identified an altered inflammatory environment leading to a defective Schwann cell response, as an underlying mechanism of impaired nerve regeneration during aging. Chronic inflammation was detected in intact uninjured old nerves, characterized by increased macrophage infiltration and raised levels of monocyte chemoattractant protein 1 (MCP1) and CC chemokine ligand 11 (CCL11). Schwann cells in the old nerves appeared partially dedifferentiated, accompanied by an activated repair program independent of injury. Upon sciatic nerve injury, an initial delayed immune response was followed by a persistent hyperinflammatory state accompanied by a diminished repair process. As a contributing factor to nerve aging, we showed that CCL11 interfered with Schwann cell differentiation in vitro and in vivo. Our results indicate that increased infiltration of macrophages and inflammatory signals diminish regenerative capacity of aging nerves by altering Schwann cell behavior. The study identifies CCL11 as a promising target for anti‐inflammatory therapies aiming to improve nerve regeneration in old age.

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Section: Resultsmentioning

confidence: 99%

Inflammaging impairs peripheral nerve maintenance and regeneration

et al. 2018

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“…Axons begin to grow into the distal endoneurial tubes 1 week after nerve injury [6,39,45] ; Schwann cell/axon contacts are re-established and remyelination occurs at about 2 weeks; and the proper target tissues are reinnervated at about 4 weeks after sciatic nerve injury. In this process, a large number of genes with marked up-or down-regulation were differentially expressed, indicating sustained regulation at consecutive time points, meaning regeneration/repair by means of a continuously progressive program [4,10,35] . Nerve regeneration mainly consists of nerve repair and tissue re-innervation after injury [45,46] .…”

Section: Discussionmentioning

confidence: 99%

“…The process of WD can be induced by autoimmune or inflammatory injuries to the axon, as well as by laceration and crush. The term WD now refers to the following events in the distal stump: injury is followed by Ca 2+ influx and axonal protease activation [3][4][5][6][7][8][9][10] ; an important process is the activation and recruitment of macrophages that respond with phagocytosis, leading to the clearance of axonal debris and myelin that is required for axonal repair or regeneration [3][4][5][6][7][8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

Expression changes and bioinformatic analysis of Wallerian degeneration after sciatic nerve injury in rat

Yao

Shen

et al. 2013

Neurosci. Bull.

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Wallerian degeneration (WD) remains an important research topic. Many genes are differentially expressed during the process of WD, but the precise mechanisms responsible for these differentiations are not completely understood. In this study, we used microarrays to analyze the expression changes of the distal nerve stump at 0, 1, 4, 7, 14, 21 and 28 days after sciatic nerve injury in rats. The data revealed 6 076 differentially-expressed genes, with 23 types of expression, specifically enriched in genes associated with nerve development and axonogenesis, cytokine biosynthesis, cell differentiation, cytokine/chemokine production, neuron differentiation, cytokinesis, phosphorylation and axon regeneration. Kyoto Encyclopedia of Genes and Genomes pathway analysis gave findings related mainly to the MAPK signaling pathway, the Jak-STAT signaling pathway, the cell cycle, cytokine-cytokine receptor interaction, the p53 signaling pathway and the Wnt signaling pathway. Some key factors were NGF, MAG, CNTF, CTNNA2, p53, JAK2, PLCB1, STAT3, BDNF, PRKC, collagen II, FGF, THBS4, TNC and c-Src, which were further validated by real-time quantitative PCR, Western blot, and immunohistochemistry. Our findings contribute to a better understanding of the functional analysis of differentially-expressed genes in WD and may shed light on the molecular mechanisms of nerve degeneration and regeneration.

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“…The partial sciatic nerve ligation (PSNL) model was used to study neuropathic pain, following the method described in rats by Seltzer et al (1990), and adapted to mice by Malmberg and Basbaum (1998). For all other experiments, a microcrush lesion of the left sciatic nerve was used as a model, following our previously published method (Boivin et al, 2007). As before, the lesion was made at midthigh level and the site of lesion was marked with a 10-0 Ethilon suture (Ethicon) passed through the epineurium only.…”

Section: Methodsmentioning

confidence: 99%

“…For experiments involving in situ hybridization (ISH), mice were overdosed with a mixture of ketamine and xylazine and (Boivin et al, 2007).…”

Section: Methodsmentioning

confidence: 99%

Functional Recovery after Peripheral Nerve Injury is Dependent on the Pro-Inflammatory Cytokines IL-1β and TNF: Implications for Neuropathic Pain

Nadeau¹,

Filali²,

Zhang³

et al. 2011

J. Neurosci.

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293

226

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IL-1␤ 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 that mRNA and protein levels of IL-1␤ and TNF are rapidly upregulated in the injured mouse sciatic nerve. Mice lacking both IL-1␤ 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-1␤ or TNF at the site of sciatic nerve injury in IL-1␤-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-1␤-, TNF-, and IL-1␤/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-1␤/ 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.

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

Cited by 218 publications

References 78 publications

Inflammaging impairs peripheral nerve maintenance and regeneration

Inflammaging impairs peripheral nerve maintenance and regeneration

Expression changes and bioinformatic analysis of Wallerian degeneration after sciatic nerve injury in rat

Functional Recovery after Peripheral Nerve Injury is Dependent on the Pro-Inflammatory Cytokines IL-1β and TNF: Implications for Neuropathic Pain

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