Consequences of differential macrophage activation after spinal cord trauma.

摘要

Spinal cord injury (SCI) elicits an immediate and robust microglial response augmented by subsequent infiltration of monocyte derived macrophages. Collectively referred to as CNS macrophages, these cells have been postulated to play both detrimental and protective roles after CNS trauma. An appreciation of macrophage heterogeneity and plasticity suggests that they do both; however concrete evidence supporting this hypothesis is limited. This is, perhaps, not surprising since CNS trauma elicits a dynamic, complex microenvironment within which it is extremely difficult to dissect out precise mechanisms of macrophage-mediated injury or repair.; Relevant in vitro models should yield insight into the potential of each CNS macrophage population to promote neuroprotection or neurotoxicity and identify effector pathways for future manipulation in vivo. For such models to be relevant, they must accurately mimic critical components of the in vivo situation. For example, if cultured cells fail to accurately represent those present in vivo , the subsequent findings are fatally flawed. Although many have used in vitro models to draw conclusions about the contribution of monocyte-derived macrophages to SCI, no one has actually characterized these cells; thus the accuracy of these conclusions remains questionable.; To develop a physiologically meaningful model for SCI-elicited, monocyte derived macrophages, we first defined the inductive potential of these cells in vivo. Specifically, we used laser capture microdissection and real time PCR to build a molecular profile for hematogenous macrophages at the onset and peak of their response to SCI. We combined these data with findings from chimeric animals to describe a comprehensive phenotype for hematogenous SCI macrophages. We then compared this phenotype to that of three commonly-studied primary macrophage populations in vitro. Resident peritoneal, elicited peritoneal, and bone marrow derived macrophages (BMDM) were not interchangeable; each population exhibited unique characteristics. Of these macrophage subtypes, only cultured BMDM adequately modeled hematogenous SCI macrophages. Further studies utilizing BMDM will allow researchers to dissect the effects of the trauma-elicited inflammatory milieu on hematogenous macrophages.; A second limitation to the study of macrophages after CNS trauma is that although microglia and monocyte derived macrophages have unique lineages and may play distinct roles after injury, these cells are morphologically identical. The only marker routinely used to differentiate microglia from peripheral macrophages is CD45; however, since both populations express this marker (albeit at different levels), the usefulness of this technique is limited. Recently, it was observed that fractalkine receptor, CX3CR1, might be differentially regulated between microglia and macrophages; others confirmed that although microglia express CX3CR1, at least some populations of peripheral macrophages do not.; We hypothesized that CX3CR1 expression might differentiate microglia from peripherally derived CNS macrophages. Accordingly, we confirmed that CX3CR1 is ubiquitously expressed by resting microglia but is present on only a subpopulation of CNS macrophages after SCI. (Abstract shortened by UMI.)