Macrophages Promote Axon Regeneration with Concurrent Neurotoxicity

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 pro-regenerative 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 killin

Hematogenous macrophages express CD8 and distribute to regions of lesion cavitation after spinal cord injury.

Historically, CD4 and CD8 antigens have been used to designate functionally distinct T-lymphocyte subsets. However, these antigens also have been described on macrophages in the normal and pathologic central nervous system (CNS). Signaling through CD4 or CD8 may impart unique functions in macrophage subsets that express these antigens. In the current study, the distribution and temporal patterns of expression of CD4 and CD8 were evaluated on various cell types within the traumatically injured spinal cord. The data reveal divergent patterns of CD4 and CD8 expression on unique macrophage populations. Specifically, we show sustained elevations of CD4 expression on microglia and macrophages throughout the lesion site and spared white matter. In contrast, CD8 is predominantly associated with hematogenous macrophages that are recruited from the blood during the first week postinjury. The distribution of CD8-positive cells is restricted to areas of necrotic cavitation. Differential signaling of resident and recruited macrophages through CD4 or CD8 may explain the apparent dichotomy of CNS-macrophage-mediated injury and repair

Cyclic AMP-specific PDEs: A promising therapeutic target for CNS repair

Research to date has indicated that cAMPspecific PDEs, particularly the members of PDE4 family, play a crucial role in the pathogenesis of CNS injury and neurodegeneration by downregulating intracellular levels of cAMP in various cell types. Reduced cAMP signaling results in immune cell activation, inflammation, secondary tissue damage, scar formation and axon growth failure, ultimately leading to an exacerbation of injury, the prevention of endogenous repair and limited functional recovery. Although inhibition of cAMPspecific-PDE activity through the use of drugs like Rolipram has been shown to reverse these deficiencies and mediate neurorepair, an inability to develop selective agents and/or reduce dose-limiting side-effects associated with PDE4 inhibition has hampered their clinical translation. Recent work with more selective pharmacological inhibitors of cAMP-specific PDEs and molecular targeting approaches, along with improved understanding of the basic biology and role of PDEs in pathological processes may enable this promising therapeutic approach to advance clinically and have a similar impact on CNS injury and disease as PDE5 inhibitors have had on the treatment of sexual dysfunction