Spinal cord injury and inflammatory mediators: Role in "fire barrier" formation and potential for neural regeneration

Abstract

Traumatic spinal cord injury result in considerable and lasting functional impairments, triggering complex inflammatory and pathological events. Spinal cord scars, often metaphorically referred to as "fire barriers," aim to control the spread of neuroinflammation during the acute phase but later hinder axon regeneration in later stages. Recent studies have enhanced our understanding of immunomodulation, revealing that injury-associated inflammation involves various cell types and molecules with positive and negative effects. This review employs bibliometric analysis to examine the literature on inflammatory mediators in spinal cord injury, highlighting recent research and providing a comprehensive overview of the current state of research and the latest advances in studies on neuroinflammation related to spinal cord injury. We summarize the immune and inflammatory responses at different stages of spinal cord injury, offering crucial insights for future research. Additionally, we review repair strategies based on inflammatory mediators for the injured spinal cord. Finally, this review discusses the current status and future directions of translational research focused on immune-targeting strategies, including pharmaceuticals, biomedical engineering, and gene therapy. The development of a combined, precise, and multitemporal strategy for the repair of injured spinal cords represents a promising direction for future research.

Keywords: axon regeneration; bibliometric analysis; central nervous system; chronic phase; conditioning lesion paradigm; glia scar; immunomodulatory pharmaceutics; inflammatory mediator; neuroinflammation; spinal cord injury; zebrafish.

Figure 1

Inclusion and exclusion processes of neuroinflammation-induced regeneration in spinal cord injury research.

Figure 2

Contribution characteristics of neuroinflammation in neuroregeneration research. (A) Annual publication volume of global studies on neuroinflammation and spinal cord injury. (B) Model-fitted curves representing the cumulative number of global publications.

Figure 3

Global collaboration networks among countries in neuroinflammation and spinal cord injury research.

Figure 4

Visualization of keywords in neuroinflammation and spinal cord injury studies. (A) Density map of keywords co-occurrence. (B) Cluster network map. Nodes of the same color form a cluster. (C) Top 20 keywords with the strongest citation bursts.

Figure 5

Spinal cord scars exhibit varying functions at different phases of spinal cord injury. In the initial acute stage of injury, the rapidly formed scar primarily serves as a physical barrier to impede the spread of inflammatory processes. During this period, infiltrating inflammatory blood cells release a substantial amount of neurotoxic agents, such as IL-6, IL-1β, TNF-α, and iNOS. These inflammatory mediators subsequently stimulate the activation of astrocytes and microglia, which contribute to the formation of scar tissue. In the later phases of injury, as illustrated in the diagram, the substantial barrier created by the scar hinders neural regeneration, thereby reducing the likelihood of successful traversing through this area. Created with BioRender.com. Arg1: Arginase 1; IL: interleukin; iNOS: inducible nitric oxide synthase; OPCs: oligodendrocyte precursor cells; PDGF: platelet-derived growth factor; TNF-α: tumor necrosis factor-α.

Figure 6

Inflammatory microenvironment changes after SCI. Alterations in local microenvironmental inflammatory factors following spinal cord injury, specifically highlighting variations in microglia, macrophages, neutrophils, and lymphocytes across the acute, subacute, and chronic phases. Created with BioRender.com. SCI: Spinal cord injury.

Figure 7

Different regeneration models of rat and zebrafish after spinal cord injury. After contusion injury, in the chronic stage, the rat’s spinal cord developed a cystic cavity wrapped by the fibrotic and glial scar. Wallerian degeneration and the accumulation of extracellular components, such as myelin-associated glycoprotein, oligodendrocyte myelin glycoprotein, and CSPG, play an inhibitory role in neurite regeneration. In contrast, the most notable difference in the zebrafish spinal cord injury repair model is that reactive glial cells migrate and adopt a bipolar morphology to fill the lesion. Ependymal-radial glial cells serve as the primary source of neurogenesis in this model. Created with BioRender.com. CSPG: Chondroitin sulfate proteoglycan; NG2-OPC: neural/glial antigen 2-positive oligodendrocyte precursor cells.