Contribution of macrophages to enhanced regenerative capacity of dorsal root ganglia sensory neurons by conditioning injury.
Although the central branches of the dorsal root ganglion (DRG) sensory neurons do not spontaneously regenerate, a conditioning peripheral injury can promote their regeneration. A potential role of macrophages in axonal regeneration was proposed, but it has not been critically addressed whether macrophages play an essential role in the conditioning injury model. After sciatic nerve injury (SNI) in rats, the number of macrophages in DRGs gradually increased by day 7. The increase persisted up to 28 d and was accompanied by upregulation of inflammatory mediators, including oncomodulin. A macrophage deactivator, minocycline, reduced the macrophage number and expressions of the inflammatory mediators. Molecular signatures of conditioning effects were abrogated by minocycline, and enhanced regenerative capacity was substantially attenuated both in vitro and in vivo. Delayed minocycline infusion abrogated the SNI-induced long-lasting heightened neurite outgrowth potential, indicating a role for macrophages in the maintenance of regenerative capacity. Intraganglionic cAMP injection also resulted in an increase in macrophages, and minocycline abolished the cAMP effect on neurite outgrowth. However, conditioned media (CM) from macrophages treated with cAMP did not exhibit neurite growth-promoting activity. In contrast, CM from neuron-macrophage cocultures treated with cAMP promoted neurite outgrowth greatly, highlighting a requirement for neuron-macrophage interactions for the induction of a proregenerative macrophage phenotype. The growth-promoting activity in the CM was profoundly attenuated by an oncomodulin neutralizing antibody. These results suggest that the neuron-macrophage interactions involved in eliciting a proregenerative phenotype in macrophages may be a novel target to induce long-lasting regenerative processes after axonal injuries in the CNS.
Brain Disease Research Center, Institute for Medical Sciences and Department of Neurology, Ajou University School of Medicine, Suwon, 443-721, Republic of Korea and Neuroscience Graduate Program, Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, 443-721, Republic of Korea.
Min Jung
MJ
Kwon
Jinha
J
Kim
Haeyoung
H
Shin
Soo Ryeong
SR
Jeong
Young Mi
YM
Kang
Jun Young
JY
Choi
Dong Hoon
DH
Hwang
Byung Gon
BG
Kim
D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002469:Cell Separation; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000378:metabolism; D018920:Coculture Techniques; D000242:Cyclic AMP / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D019922:GAP-43 Protein / Q000235:genetics / Q000378:metabolism; D005727:Ganglia, Spinal / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D008840:Microfilament Proteins / Q000378:metabolism; D008911:Minocycline / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D009416:Nerve Regeneration / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000473:pathology* / Q000503:physiopathology; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology*
C100745:Aif1 protein, rat; D002135:Calcium-Binding Proteins; D016207:Cytokines; D019922:GAP-43 Protein; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D009414:Nerve Growth Factors; D002772:Cholera Toxin; D000242:Cyclic AMP; D008911:Minocycline