Abstract
Traumatic spinal cord injury (SCI) elicits an acute inflammatory response which comprises numerous cell populations. It is driven by the immediate response of macrophages and microglia, which triggers activation of genes responsible for the dysregulated microenvironment within the lesion site and in the spinal cord parenchyma immediately adjacent to the lesion. Recently published data indicate that microglia induces astrocyte activation and determines the fate of astrocytes. Conversely, astrocytes have the potency to trigger microglial activation and control their cellular functions. Here we review current information about the release of diverse signaling molecules (pro-inflammatory vs. anti-inflammatory) in individual cell phenotypes (microglia, astrocytes, blood inflammatory cells) in acute and subacute SCI stages, and how they contribute to delayed neuronal death in the surrounding spinal cord tissue which is spared and functional but reactive. In addition, temporal correlation in progressive degeneration of neurons and astrocytes and their functional interactions after SCI are discussed. Finally, the review highlights the time-dependent transformation of reactive microglia and astrocytes into their neuroprotective phenotypes (M2a, M2c and A2) which are crucial for spontaneous post-SCI locomotor recovery. We also provide suggestions on how to modulate the inflammation and discuss key therapeutic approaches leading to better functional outcome after SCI.
Highlights
Spinal cord injury (SCI) is one of the most devastating events leading to serious neurological deficits
The authors did not find a significant difference in immunoreactivity levels of neurofilament M or H at lesion site from huperzine A (HUP-A)-treated and control rats. All these findings support the hypothesis that chronic administration of HUP-A does not introduce further toxicity in the injured spinal cord, and that HUP-A treatment, not triggering axonal regeneration, protects myelin against the chronic damage resulting from neuroinflammation that is mediated largely by locally activated microglia and astroglia and by macrophage invasion [95]
DCX+ cells were positive for neuronal marker TUBB3 (Tubulin Beta 3 Class III). These data indicate that neurogenesis can be induced by SOX2 in an injured environment of the adult spinal cord. These results show that SOX2-induced adult neurogenesis can generate mature neurons with features of GABAergic interneurons in injured valproic acid (VPA)-treated spinal cords
Summary
Spinal cord injury (SCI) is one of the most devastating events leading to serious neurological deficits. Inflammatory response is one of the key mechanisms of secondary injury It includes activation of resident cells (microglia, astrocytes) and recruitment of immune cells (macrophages and neutrophils) from the bloodstream to the injury site. Resident and immune cells release proinflammatory cytokines, including interleukins (IL-1, IL-6) and tumor necrosis factor-α (TNFα), all of which increase the extent of the inflammatory response These events play an important role in secondary tissue damage and cell death. To develop appropriately targeted repair strategies, there is a need for detailed understanding of how various cell populations interact with each other within the lesion site and in the surrounding spinal cord tissue in both acute and subacute phases of SCI. Some other promising strategies for spinal cord repair will be discussed separately
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