Abstract
By causing damage to neural networks, spinal cord injuries (SCI) often result in severe motor and sensory dysfunction. Functional recovery requires axonal regrowth and regeneration of neural network, processes that are quite limited in the adult central nervous system (CNS). Previous work has shown that SCI lesions contain an accumulation of activated microglia, which can have multiple pathophysiological influences. Here, we show that activated microglia inhibit axonal growth via repulsive guidance molecule a (RGMa). We found that microglia activated by lipopolysaccharide (LPS) inhibited neurite outgrowth and induced growth cone collapse of cortical neurons in vitro—a pattern that was only observed when there was direct contact between microglia and neurons. After microglia were activated by LPS, they increased expression of RGMa; however, treatment with RGMa-neutralizing antibodies or transfection of RGMa siRNA attenuated the inhibitory effects of microglia on axonal outgrowth. Furthermore, minocycline, an inhibitor of microglial activation, attenuated the effects of microglia and RGMa expression. Finally, we examined whether these in vitro patterns could also be observed in vivo. Indeed, in a mouse SCI model, minocycline treatment reduced the accumulation of microglia and decreased RGMa expression after SCI, leading to reduced dieback in injured corticospinal tracts. These results suggest that activated microglia play a major role in inhibiting axon regeneration via RGMa in the injured CNS.
Highlights
Spinal cord injuries (SCI) often have devastating impacts on neural function, leading to reductions in motor and sensory abilities
To assess the effect of microglia or macrophage on the neurons, we employed co-culture assay consisting of cortical neurons (E18) and microglia/ macrophage in vitro
These results suggest that activated primary microglia, but not Bone marrow-derived macrophages (BMDM) or unactivated microglia, inhibit neurite growth and induce growth cone collapse
Summary
Spinal cord injuries (SCI) often have devastating impacts on neural function, leading to reductions in motor and sensory abilities These can be compensated for via regeneration of neurons and their axons; axonal regeneration in the adult central nervous system (CNS) is quite limited due to the presence of a number of axon growth inhibitors. SCI causes extensive inflammation and the invasion of a large number of microglia/macrophages to the epicenter of the lesion It is currently unclear whether this influx of cells plays a protective or a detrimental role during recovery [4,5,6,7,8,9]. The key molecules involved in these processes have yet to be determined
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