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Role of IL-10 in Resolution of Inflammation and Functional Recovery after Peripheral Nerve Injury. J Neurosci 2015 Dec 16;35(50):16431-42 PMID: 26674868

Abstract

UNLABELLED: 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.

SIGNIFICANCE STATEMENT: 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.

Author List

Siqueira Mietto B, Kroner A, Girolami EI, Santos-Nogueira E, Zhang J, David S

Author

Antje Kroner-Milsch MD, PhD Assistant Professor in the Neurosurgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Axons
Bone Marrow Cells
Fluorescent Antibody Technique
Inflammation
Interleukin-10
Lipopolysaccharides
Macrophages
Male
Mice
Mice, Inbred BALB C
Mice, Knockout
Movement Disorders
Myelin Proteins
Nerve Crush
Phagocytosis
Recovery of Function
Sciatic Nerve
Sensation Disorders



View this publication's entry at the Pubmed website PMID: 26674868
jenkins-FCD Prod-130 96200611f8481f0aa4f84230b11dd74d063847a3