title: Toll-like receptor signaling is critical for Wallerian degeneration and functional recovery after peripheral nerve injury.
abstract: 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-1beta 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.
authors.affiliation: Laboratory of Molecular Endocrinology, CHUL Research Center, and Department of Anatomy and Physiology, Faculty of Medicine, Laval University, Ste-Foy, Québec, Canada G1V 4G2.
authors.forename: Audrey
authors.initials: A
authors.lastname: Boivin
authors.forename: Isabelle
authors.initials: I
authors.lastname: Pineau
authors.forename: Benoit
authors.initials: B
authors.lastname: Barrette
authors.forename: Mohammed
authors.initials: M
authors.lastname: Filali
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vallières
authors.forename: Serge
authors.initials: S
authors.lastname: Rivest
authors.forename: Steve
authors.initials: S
authors.lastname: Lacroix
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000235:genetics; D007113:Immunity, Innate / Q000235:genetics; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology; D009416:Nerve Regeneration / Q000235:genetics; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000378:metabolism* / Q000503:physiopathology; D010587:Phagocytosis / Q000235:genetics; D051381:Rats; D020127:Recovery of Function / Q000235:genetics*; D020426:Sciatic Neuropathy / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction / Q000235:genetics*; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D014855:Wallerian Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D053583:Interleukin-1beta; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors