RAGE modulates peripheral nerve regeneration via recruitment of both inflammatory and axonal outgrowth pathways

• DOI: 10.1096/fj.04-1900com
• Publication Date: 2004-12-02T19:28:25Z
• Authors: Ling Ling Rong; Shi‐Fang Yan; Thoralf Wendt; Diana Hans; Sophia Pachydaki; Loredana G. Bucci...; Adebukola Adebayo; Wu Qu; Yan Lu; Konstantin Kostov; Evanthia Lalla; Shi Du Yan; Clifton Gooch; Matthias Szabolcs; Werner Trojaborg; Arthur P. Hays; Ann Marie Schmidt
• Keywords: Neurons; STAT3 Transcription Factor; 0301 basic medicine; Phagocytes; Nerve Crush; Receptor for Advanced Glycation End Products; Mice, Transgenic; Sciatic nerve; Signal transduction; Transgenic mice;; Sciatic Nerve; Nerve Regeneration; DNA-Binding Proteins; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Cell Movement; Mutation; Neurites; Trans-Activators; Animals; Receptors, Immunologic; Extracellular Signal-Regulated MAP Kinases; Signal Transduction

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.