Macrophages Promote Axon Regeneration with Concurrent Neurotoxicity

Abstract

Activated macrophages can promote regeneration of CNS axons. However, macrophages also release factors that kill neurons. These opposing functions are likely induced simultaneously but are rarely considered together in the same experimental preparation. A goal of this study was to unequivocally document the concurrent neurotoxic and neuroregenerative potential of activated macrophages. To do so, we quantified the length and magnitude of axon growth from enhanced green fluorescent protein-expressing dorsal root ganglion (DRG) neurons transplanted into the spinal cord in relationship to discrete foci of activated macrophages. Macrophages were activated via intraspinal injections of zymosan, a potent inflammatory stimulus known to increase axon growth and cause neurotoxicity. Using this approach, a significant increase in axon growth up to macrophage foci was evident. Within and adjacent to macrophages, DRG and spinal cord axons were destroyed. Macrophage toxicity became more evident when zymosan was injected closer to DRG soma. Under these conditions, DRG neurons were killed or their ability to extend axons was dramatically impaired. The concurrent induction of proregenerative and neurotoxic functions in zymosan-activated macrophages (ZAMs) was confirmed in vitro using DRG and cortical neurons. Importantly, the ability of ZAMs to stimulate axon growth was transient; prolonged exposure to factors produced by ZAMs enhanced cell death and impaired axon growth in surviving neurons. Lipopolysaccharide, another potent macrophage activator, elicited a florid macrophage response, but without enhancing axon growth or notable toxicity. Together, these data show that a single mode of activation endows macrophages with the ability to simultaneously promote axon regeneration and cell killing.

A Toll-Like Receptor 9 Antagonist Improves Bladder Function and White Matter Sparing in Spinal Cord Injury

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Oncomodulin links inflammation to optic nerve regeneration

“…The innate immune response in the central nervous system (CNS) is mediated by resident microglia, astrocytes, and infiltrating macrophages and neutrophils that can release numerous anti-and pro-inflammatory cytokines, chemokines, growth factors, and other signals. Although some of these factors are toxic to neurons, inflammation has been shown to promote axon regeneration and/or enhance cell survival in the optic nerve (5-9), dorsal roots (10,11), and spinal cord (12,13,14) after injury. In the optic nerve, a CNS pathway that normally shows little capacity to regenerate when injured, peripheral nerve implants into the eye, lens injury, or intraocular injections of zymosan all cause macrophages to enter the eye and stimulate retinal ganglion cells (RGCs) to regenerate lengthy axons beyond the injury site (7,8,15).…”

Microglial Toll-like Receptor 2 Contributes to Kainic Acid-induced Glial Activation and Hippocampal Neuronal Cell Death

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