RAGE modulates peripheral nerve regeneration via recruitment of both inflammatory and axonal outgrowth pathways.
Axotomy of peripheral nerve stimulates events in multiple cell types that initiate a limited inflammatory response to axonal degeneration and simultaneous outgrowth of neurites into the distal segments after injury. We found that pharmacological blockade of RAGE impaired peripheral nerve regeneration in mice subjected to RAGE blockade and acute crush of the sciatic nerve. As our studies revealed that RAGE was expressed in axons and in infiltrating mononuclear phagocytes upon injury, we tested the role of RAGE in these distinct cell types on nerve regeneration. Transgenic mice expressing signal transduction-deficient RAGE in mononuclear phagocytes or peripheral neurons were generated and subjected to unilateral crush injury to the sciatic nerve. Transgenic mice displayed decreased functional and morphological recovery compared with littermate controls, as assessed by motor and sensory conduction velocities; and myelinated fiber density. In double transgenic mice expressing signal transduction deficient RAGE in both mononuclear phagocytes and peripheral neurons, regeneration was even further impaired, suggesting the critical interplay between RAGE-modulated inflammation and neurite outgrowth in nerve repair. These findings suggest that RAGE signaling in inflammatory cells and peripheral neurons plays an important role in plasticity of the peripheral nervous system.
Rong
Ling Ling
LL
Departments of Surgery, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
Yan
Shi-Fang
SF
Wendt
Thoralf
T
Hans
Diana
D
Pachydaki
Sophia
S
Bucciarelli
Loredana G
LG
Adebayo
Adebukola
A
Qu
Wu
W
Lu
Yan
Y
Kostov
Konstantin
K
Lalla
Evanthia
E
Yan
Shi Du
SD
Gooch
Clifton
C
Szabolcs
Matthias
M
Trojaborg
Werner
W
Hays
Arthur P
AP
Schmidt
Ann Marie
AM
D000818:Animals; D002465:Cell Movement; D004268:DNA-Binding Proteins / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000276:immunology; D016501:Neurites / Q000648:ultrastructure; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D010586:Phagocytes / Q000378:metabolism / Q000502:physiology*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology*; D050796:STAT3 Transcription Factor; D012584:Sciatic Nerve / Q000166:cytology / Q000293:injuries* / Q000502:physiology; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism
D004268:DNA-Binding Proteins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D048049:Extracellular Signal-Regulated MAP Kinases