title: Role of IL-10 in Resolution of Inflammation and Functional Recovery after Peripheral Nerve Injury.
abstract: A rapid proinflammatory response after peripheral nerve injury is required for clearance of tissue debris (Wallerian degeneration) and effective regeneration. Unlike the CNS, this response is rapidly terminated in peripheral nerves starting between 2 and 3 weeks after crush injury. We examined the expression and role of the anti-inflammatory cytokine IL-10 in the resolution of inflammation and regeneration after sciatic nerve crush injury in mice. IL-10 mRNA increased over the first 7 d after injury, whereas at the protein level, immunofluorescence labeling showed IL-10(+) cells increased almost 3-fold in the first 3 weeks, with macrophages being the major cell type expressing IL-10. The role of IL-10 in nerve injury was assessed using IL-10-null mice. Increased numbers of macrophages were found in the distal segment of IL-10-null mice at early (3 d) and late (14 and 21 d) time points, suggesting that IL-10 may play a role in controlling the early influx and the later efflux of macrophages out of the nerve. A chemokine/cytokine PCR array of the nerve 24 h after crush showed a 2- to 4-fold increase in the expression of 10 proinflammatory mediators in IL-10(-/-) mice. In addition, myelin phagocytosis in vitro by LPS stimulated bone-marrow-derived macrophages from IL-10-null mice failed to downregulate expression of proinflammatory chemokines/cytokines, suggesting that IL-10 is required for the myelin-phagocytosis-induced shift of macrophages from proinflammatory to anti-inflammatory/pro-repair phenotype. The failure to switch off inflammation in IL-10-null mice was accompanied by impaired axon regeneration and poor recovery of motor and sensory function.
  
  
  CONCLUSIONS
  An appropriately regulated inflammatory response after peripheral nerve injury is essential for axon regeneration and recovery. The aim of this study was to investigate the expression and role of the anti-inflammatory cytokine IL-10 in terminating inflammation after sciatic nerve crush injury and promoting regeneration. IL-10 is rapidly expressed by macrophages after crush injury. Its role was assessed using IL-10-null mice, which showed that IL-10 plays a role in controlling the early influx and the later efflux of macrophages out of the injured nerve, reduces the expression of proinflammatory chemokines and cytokines, and is required for myelin-phagocytosis-induced shift of macrophages from proinflammatory to anti-inflammatory. Furthermore, lack of IL-10 leads to impaired axon regeneration and poor recovery of motor and sensory function.
authors.affiliation: Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada H3G 1A4, Institute of Biomedical Sciences, Centre of Health Sciences, Federal University of Rio de Janeiro, Brazil 21941902, and.
authors.forename: Bruno
authors.initials: B
authors.lastname: Siqueira Mietto
authors.affiliation: Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada H3G 1A4.
authors.forename: Antje
authors.identifier: http://orcid.org/0000-0001-5897-9774
authors.initials: A
authors.lastname: Kroner
authors.affiliation: Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada H3G 1A4.
authors.forename: Elizabeth I
authors.initials: EI
authors.lastname: Girolami
authors.affiliation: Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada H3G 1A4.
authors.forename: Eva
authors.identifier: http://orcid.org/0000-0002-5917-3534
authors.initials: E
authors.lastname: Santos-Nogueira
authors.affiliation: Neurology and Neurosurgery, Alan Edwards Centre for Research on Pain, and Faculty of Dentistry, McGill University, Montreal Quebec, Canada H3A 0G1.
authors.forename: Ji
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada H3G 1A4, sam.david@mcgill.ca.
authors.forename: Samuel
authors.initials: S
authors.lastname: David
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D007249:Inflammation / Q000473:pathology*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009069:Movement Disorders / Q000209:etiology / Q000235:genetics; D009185:Myelin Proteins / Q000235:genetics; D009409:Nerve Crush; D059348:Peripheral Nerve Injuries / Q000473:pathology*; D010587:Phagocytosis / Q000235:genetics; D020127:Recovery of Function; D012584:Sciatic Nerve / Q000293:injuries; D012678:Sensation Disorders / Q000209:etiology / Q000235:genetics
chemical_list: C556062:IL10 protein, mouse; D008070:Lipopolysaccharides; D009185:Myelin Proteins; D016753:Interleukin-10
keywords: IL-10; anti-inflammatory cytokine; inflammation; macrophage; peripheral nerve; regeneration