Inflammation after spinal cord injury: a review of the critical timeline of signaling cues and cellular infiltration

Abstract

Traumatic spinal cord injury (SCI) is a devastating neurological condition that results in a loss of motor and sensory function. Although extensive research to develop treatments for SCI has been performed, to date, none of these treatments have produced a meaningful amount of functional recovery after injury. The primary injury is caused by the initial trauma to the spinal cord and results in ischemia, oxidative damage, edema, and glutamate excitotoxicity. This process initiates a secondary injury cascade, which starts just a few hours post-injury and may continue for more than 6 months, leading to additional cell death and spinal cord damage. Inflammation after SCI is complex and driven by a diverse set of cells and signaling molecules. In this review, we utilize an extensive literature survey to develop the timeline of local immune cell and cytokine behavior after SCI in rodent models. We discuss the precise functional roles of several key cytokines and their effects on a variety of cell types involved in the secondary injury cascade. Furthermore, variations in the inflammatory response between rats and mice are highlighted. Since current SCI treatment options do not successfully initiate functional recovery or axonal regeneration, identifying the specific mechanisms attributed to secondary injury is critical. With a more thorough understanding of the complex SCI pathophysiology, effective therapeutic targets with realistic timelines for intervention may be established to successfully attenuate secondary damage.

Keywords: Astrocytes; Cytokines; Inflammation; Macrophages; Microglia; Secondary cascade; Spinal cord injury.

Fig. 1

Flowchart displaying how articles were screened to be analyzed for assessing cytokine/chemokine regulation after SCI. All studies used were performed in rats and mice and assessed local cytokine/chemokine regulation at specific times post-injury compared to uninjured or sham controls

Fig. 2

Depiction of cytokine regulation following SCI in rodent models. A literature search was conducted and relevant data regarding significant cytokine regulation was collected at various timepoints. Data is presented as a percentage of studies that found significant changes in cytokine protein or mRNA expression levels compared to sham or naïve controls (p < 0.05). The number of papers used for each timepoint is listed at the top of each bar. A Changes in IL-1β levels after SCI [, , , , –, –, –, , –, , , , –187]. The proinflammatory cytokine IL-1β shows consistent upregulation in the acute phase following SCI. However, there are some discrepancies as to whether IL-1β remains upregulated several days after injury and the second surge 14 days was only observed in mice. B Changes in TNFɑ levels after SCI [, –, –, –, , –, –, , , –, –189]. The majority of studies show an upregulation of the proinflammatory cytokine TNFɑ immediately following SCI and persisting several days after injury. C Changes in IL-6 levels after SCI [, , , –, , , –, , , –, , , , , , , , , , , , –189]. Consistent upregulation of the proinflammatory cytokine is seen in the first 24 h following injury before returning to baseline levels by 7-day post-injury. D Changes in IL-1ɑ levels after SCI [17, 38, 40, 66, 84, 87, 90, 95]. The proinflammatory cytokine IL-1ɑ is upregulated in a similar manner to its isoform IL-1β, though IL-1β plays a more significant role following SCI [132, 133]. E Changes in IFN-γ levels after SCI [17, 38, 48, 87, 90, 95]. The relative change in IFN-γ expression following SCI remains controversial, as shown by the conflicting data presented. It appears to be upregulated in mice and downregulated in rats after 24 h. F Changes in MCP-1 levels after SCI [, , , , , –90, 93, 121]. While there is some debate surrounding the regulation of the MCP-1 chemokine immediately after injury (1 h to < 6 h), nearly all data collected shows that MCP-1 expression levels elevate quickly and remain upregulated for several days. G Changes in IL-10 levels after SCI [, , , , , , , –, , , –176]. A delayed response is seen with IL-10 showing mixed results until upregulation at 3–7 days after injury. The anti-inflammatory cytokine returns to baseline levels by 14 days. H Changes in IL-4 levels after SCI [7, 17, 38, 47, 48, 66, 70, 87]. While some studies show increased expression of the anti-inflammatory IL-4, most researchers did not observe a change in IL-4 levels. I Changes in IL-13 levels after SCI [17, 38, 47, 48, 87, 90]. Previous studies display conflicting data surrounding the regulation of IL-13 after injury, where it was upregulated in mice and downregulated in rats 3 days hours post-injury

Fig. 3

Line graph displaying the percentage of studies that observed significant upregulation in IL-1β, TNFα, IL-6, and IL-10. The majority of investigators observe a significant upregulation of the three most investigated inflammatory cytokines early after injury and TNFα and IL-1β remain upregulated. The anti-inflammatory cytokine IL-10 lags further behind and the majority of investigators show it peaking around 1-week post-injury

Fig. 4

Primary injury after SCI causes cell membrane disruption and rupture of blood vessels leading to secondary injury with extensive upregulation of cytokines/chemokines and infiltration of immune cells. Microglia, the resident macrophages, are early responders and become indistinguishable in terms of morphology from peripherally derived macrophages. In rats, neutrophils peak early in the injury at around 24 h and gradually decrease over the next 7–10 days, while lymphocytes peak at lower levels and at a much later time. Pericytes also infiltrate later and interact with microglia around the edges of the injury and this entire injury site is encased by activated astrocytes

Fig. 5

Diagram displaying cellular activation/infiltration after rat SCI. After the primary insult, there is a much larger secondary injury with extensive infiltration of immune cells. Neutrophil infiltration peaks 24-h post-injury and decreases over the next week. Infiltrating lymphocytes accumulate around blood vessels in gray matter as early as 6 h and T-cell specific lymphocytes peak around 9-day post-injury. Microglia are activated, retracting their cytoplasmic processes and becoming indistinguishable in terms of morphology from the infiltrating PDMs. The astrocytes also become reactive and retract the cytoplasmic processes and migrate to the lesion. Although initially the astrocytes aid in tissue repair, they eventually become scar-forming astrocytes and begin to wall off the ensuing inflammation. The final glial scar is compartmentalized with infiltrating immune cells in the center, microglia interacting with pericytes around the edges, and astrocytes encapsulating the entire tissue containing the inflammatory cells