Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury

Traumatic injury to the spinal cord initiates a series of destructive cellu lar processes which accentuate tissue damage at and beyond the original sit e of trauma. The cellular inflammatory response has been implicated as one mechanism of secondary degeneration. Of the various leukocytes present in t he spinal cord after injury, macrophages predominate. Through the release o f chemicals and enzymes involved in host defense, macrophages can damage ne urons and glia. However, macrophages are also essential for the reconstruct ion of injured tissues. This apparent dichotomy in macrophage function is f urther complicated by the overlapping influences of resident microglial-der ived macrophages and those phagocytes that are derived from peripheral sour ces. To clarify the role macrophages play in posttraumatic secondary degene ration, we selectively depleted peripheral macrophages in spinal-injured ra ts during a time when inflammation has been shown to be maximal. Standardiz ed behavioral and neuropathological analyses (open-field locomotor function , morphometric analysis of the injured spinal cord) were used to evaluate t he efficacy of this treatment. Beginning 24 h after injury and then again a t days 3 and 6 postinjury, spinal cord-injured rats received intravenous in jections of liposome-encapsulated clodronate to deplete peripheral macropha ges. Within the spinal cords of rats treated in this fashion, macrophage in filtration was significantly reduced at the site of impact. These animals s howed marked improvement in hindlimb usage during overground locomotion. Be havioral recovery was paralleled by a significant preservation of myelinate d axons, decreased cavitation in the rostrocaudal axis of the spinal cord, and enhanced sprouting and/or regeneration of axons at the site of injury. These data implicate hematogenous (blood-derived) macrophages as effecters of acute secondary injury. Furthermore, given the selective nature of the d epletion regimen and its proven efficacy when administered after injury, ce ll-specific immunomodulation may prove useful as an adjunct therapy after s pinal cord injury. (C) 1999 Academic Press.