Another Barrier to Regeneration in the CNS: Activated Macrophages Induce Extensive Retraction of Dystrophic Axons through Direct Physical Interactions

Abstract

Injured axons of the adult CNS undergo lengthy retraction from the initial site of axotomy after spinal cord injury. Macrophage infiltration correlates spatiotemporally with this deleterious phenomenon, but the direct involvement of these inflammatory cells has not been demonstrated. In the present study, we examined the role of macrophages in axonal retraction within the dorsal columns after spinal cord injury in vivo and found that retraction occurred between days 2 and 28 after lesion and that the ends of injured axons were associated with ED-1ϩ cells. Clodronate liposome-mediated depletion of infiltrating macrophages resulted in a significant reduction in axonal retraction; however, we saw no evidence of regeneration. We used time-lapse imaging of adult dorsal root ganglion neurons in an in vitro model of the glial scar to examine macrophage-axon interactions and observed that adhesive contacts and considerable physical interplay between macrophages and dystrophic axons led to extensive axonal retraction. The induction of retraction was dependent on both the growth state of the axon and the activation state of the macrophage. Only dystrophic adult axons were susceptible to macrophage "attack." Unlike intrinsically active cell line macrophages, both primary macrophages and microglia required activation to induce axonal retraction. Contact with astrocytes had no deleterious effect on adult dystrophic axons, suggesting that the induction of extensive retraction was specific to phagocytic cells. Our data are the first to indicate a direct role of activated macrophages in axonal retraction by physical cell-cell interactions with injured axons.

p53 Regulates the Neuronal Intrinsic and Extrinsic Responses Affecting the Recovery of Motor Function following Spinal Cord Injury

“…A previous study suggested an increase in NF-B-dependent transcription of several proinflammatory targets in p53 Ϫ/Ϫ macrophages (Komarova et al, 2005); however, we found that the postinjury gene expression of IL-1␤, IL-6, and TNF␣ in the spinal cord was not affected by the absence of p53 (data not shown). Recent reports have indicated that, in a contusion spinal injury model, there is a predominance of classically activated or M1 macrophages at chronic stages after SCI and they contribute to the inhibition of axon regrowth (Kigerl et al, 2009) and to increased axon dieback (Horn et al, 2008), while M2 macrophages were shown to be neuroprotective in comparison. Interestingly, certain M2 subtypes have been associated with wound healing, matrix remodeling, and fibrosis (Wynn and Barron, 2010).…”

Regeneration of axons in injured spinal cord by activation of bone morphogenetic protein/Smad1 signaling pathway in adult neurons

“…The phenotype could in part be caused by a lack of axonal dieback of neurons with AAV-BMP4 treatment, as has been shown in conditioned adult neurons (34,35). However, there seems to be genuine axonal regrowth: some axons did extend further rostrally, beyond the transection site, and even emerged from the rostral border of the lesion site.…”

Emerging Concepts in Myeloid Cell Biology after Spinal Cord Injury

“…Neutrophils can exacerbate hemorrhage, leading to more extensive pathology after SCI [21,22]; however, these same cells may also trigger the onset of wound healing cascades in the injured spinal cord [23]. Similarly, microglia and macrophages can promote CNS repair (e.g., phagocytic removal of growth-inhibitory debris; stimulate neurite outgrowth) or exacerbate cell death and axonal degeneration at the site of injury [24][25][26]. The roles of dendritic cells and MDSCs are less welldefined.…”

“…When KCs are depleted via systemic injection of clodronate liposomes, accumulation of neutrophils in the injured brain or spinal cord is significantly reduced [63]. This may partially explain why post-injury intravenous delivery of clodronate liposomes confers neuroprotection and promotes recovery of function after SCI [26,64,65].…”