Antagonism of RAGE suppresses peripheral nerve regeneration.
Axotomy of peripheral nerve triggers events that coordinate a limited inflammatory response to axonal degeneration and initiation of neurite outgrowth. Inflammatory and neurite outgrowth-promoting roles for the receptor for advanced glycation end products (RAGE) have been suggested, so we tested its role in peripheral nerve regeneration. Analysis of immunohistochemical localization of RAGE by confocal microscopy revealed that RAGE was expressed in axons and infiltrating mononuclear phagocytes upon unilateral sciatic nerve crush in mice. Administration of soluble RAGE, the extracellular ligand binding domain of RAGE, or blocking F(ab')2 fragments of antibodies raised to either RAGE or its ligands, S100/calgranulins or amphoterin, reduced functional recovery as assessed by motor and sensory nerve conduction velocities and sciatic functional index and reduced regeneration, as assessed by myelinated fiber density after acute crush of the sciatic nerve. In parallel, in mice subjected to RAGE blockade, decreased numbers of mononuclear phagocytes infiltrated the distal nerve segments after crush. These findings provide the first evidence of an innate function of the ligand/RAGE axis and suggest that RAGE plays an important role in regeneration of the peripheral nervous system.
Rong
Ling Ling
LL
Department of Surgery, Columbia University Medical Center, New York, New York 10032, USA.
Trojaborg
Werner
W
Qu
Wu
W
Kostov
Konstantin
K
Yan
Shi Du
SD
Gooch
Clifton
C
Szabolcs
Matthias
M
Hays
Arthur P
AP
Schmidt
Ann Marie
AM
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000187:drug effects; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology*; D012584:Sciatic Nerve / Q000166:cytology / Q000293:injuries* / Q000502:physiology
D000906:Antibodies; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic