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The Journal of Neuroscience, August 12, 2009, 29(32):9967-9976; doi:10.1523/JNEUROSCI.1151-09.2009

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Development/Plasticity/Repair
Overcoming Macrophage-Mediated Axonal Dieback Following CNS Injury

Sarah A. Busch,^1 * Kevin P. Horn,^1 * Daniel J. Silver,² and Jerry Silver¹

¹Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106, and ²Department of Neuroscience, College of Medicine, University of Florida, Gainesville, Florida 32611

Correspondence should be addressed to Dr. Jerry Silver, Department of Neurosciences, Case Western Reserve University, 2109 Adelbert Road, SOM E-658, Cleveland, Ohio 44106. Email: jxs10{at}cwru.edu

Trauma to the adult CNS initiates multiple processes including primary and secondary axotomy, inflammation, and glial scar formation that have devastating effects on neuronal regeneration. After spinal cord injury, the infiltration of phagocytic macrophages coincides with long-distance axonal retraction from the initial site of injury, a deleterious phenomenon known as axonal dieback. We have previously shown that activated macrophages directly induce long-distance retraction of dystrophic axons in an in vitro model of the glial scar. We hypothesized that treatments that are primarily thought to increase neuronal regeneration following spinal cord injury may in fact derive a portion of their beneficial effects from inhibition of macrophage-mediated axonal retraction. We analyzed the effects of protease inhibition, substrate modification, and neuronal preconditioning on macrophage-axon interactions using our established in vitro model. General inhibition of matrix metalloproteinases and specific inhibition of MMP-9 prevented macrophage-induced axonal retraction despite significant physical interactions between the two cell types, whereas inhibition of MMP-2 had no effect. Chondroitinase ABC-mediated digestion of the aggrecan substrate also prevented macrophage-induced axonal retraction in the presence of extensive macrophage-axon interactions. The use of a conditioning lesion to stimulate intrinsic neuronal growth potential in the absence of substrate modification likewise prevented macrophage-induced axonal retraction in vitro and in vivo following spinal cord injury. These data provide valuable insight into the cellular and molecular mechanisms underlying macrophage-mediated axonal retraction and demonstrate modifications that can alleviate the detrimental effects of this unfavorable phenomenon on the postlesion CNS.

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Received Jan. 28, 2009; revised April 30, 2009; accepted June 16, 2009.

Correspondence should be addressed to Dr. Jerry Silver, Department of Neurosciences, Case Western Reserve University, 2109 Adelbert Road, SOM E-658, Cleveland, Ohio 44106. Email: jxs10{at}cwru.edu

This article has been cited by other articles:

				K. A. Kigerl, J. C. Gensel, D. P. Ankeny, J. K. Alexander, D. J. Donnelly, and P. G. Popovich Identification of Two Distinct Macrophage Subsets with Divergent Effects Causing either Neurotoxicity or Regeneration in the Injured Mouse Spinal Cord J. Neurosci., October 28, 2009; 29(43): 13435 - 13444. [Abstract] [Full Text] [PDF]

				C. Mason The Development of Developmental Neuroscience J. Neurosci., October 14, 2009; 29(41): 12735 - 12747. [Full Text] [PDF]

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