title: CCL2 Mediates Neuron-Macrophage Interactions to Drive Proregenerative Macrophage Activation Following Preconditioning Injury.
abstract: CNS neurons in adult mammals do not spontaneously regenerate axons after spinal cord injury. Preconditioning peripheral nerve injury allows the dorsal root ganglia (DRG) sensory axons to regenerate beyond the injury site by promoting expression of regeneration-associated genes. We have previously shown that peripheral nerve injury increases the number of macrophages in the DRGs and that the activated macrophages are critical to the enhancement of intrinsic regeneration capacity. The present study identifies a novel chemokine signal mediated by CCL2 that links regenerating neurons with proregenerative macrophage activation. Neutralization of CCL2 abolished the neurite outgrowth activity of conditioned medium obtained from neuron-macrophage cocultures treated with cAMP. The neuron-macrophage interactions that produced outgrowth-promoting conditioned medium required CCL2 in neurons and CCR2/CCR4 in macrophages. The conditioning effects were abolished in CCL2-deficient mice at 3 and 7 d after sciatic nerve injury, but CCL2 was dispensable for the initial growth response and upregulation of GAP-43 at the 1 d time point. Intraganglionic injection of CCL2 mimicked conditioning injury by mobilizing M2-like macrophages. Finally, overexpression of CCL2 in DRGs promoted sensory axon regeneration in a rat spinal cord injury model without harmful side effects. Our data suggest that CCL2-mediated neuron-macrophage interaction plays a critical role for amplification and maintenance of enhanced regenerative capacity by preconditioning peripheral nerve injury. Manipulation of chemokine signaling mediating neuron-macrophage interactions may represent a novel therapeutic approach to promote axon regeneration after CNS injury.
authors.affiliation: Department of Brain Science, Neuroscience Graduate Program, Department of Biomedical Sciences.
authors.forename: Min Jung
authors.initials: MJ
authors.lastname: Kwon
authors.affiliation: Department of Brain Science, Neuroscience Graduate Program, Department of Biomedical Sciences.
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Shin
authors.affiliation: Department of Brain Science, Neuroscience Graduate Program, Department of Biomedical Sciences.
authors.forename: Yuexian
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Neuroscience Graduate Program, Department of Biomedical Sciences, Department of Biomedical Informatics, and.
authors.forename: Hyosil
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Brain Science, Neuroscience Graduate Program, Department of Biomedical Sciences.
authors.forename: Anh Hong Le
authors.initials: AH
authors.lastname: Thi
authors.affiliation: Department of Brain Science, Neuroscience Graduate Program, Department of Biomedical Sciences, Department of Neurology, Ajou University School of Medicine, Suwon 443-721, Republic of Korea.
authors.forename: Jun Young
authors.initials: JY
authors.lastname: Choi
authors.affiliation: Department of Brain Science.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Kim
authors.affiliation: Department of Brain Science.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Hwang
authors.affiliation: Department of Brain Science, Neuroscience Graduate Program, Department of Biomedical Sciences, Department of Neurology, Ajou University School of Medicine, Suwon 443-721, Republic of Korea kimbg@ajou.ac.kr.
authors.forename: Byung Gon
authors.identifier: http://orcid.org/0000-0003-2233-9569
authors.initials: BG
authors.lastname: Kim
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D002772:Cholera Toxin / Q000378:metabolism; D018920:Coculture Techniques; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009416:Nerve Regeneration / Q000235:genetics* / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016501:Neurites / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology; D059348:Peripheral Nerve Injuries / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D009419:Nerve Tissue Proteins; D054390:Receptors, CCR2; D049452:Green Fluorescent Proteins; D002772:Cholera Toxin
keywords: CCL2; axon regeneration; cAMP; chemokine; macrophage; neuron–macrophage interaction