The Inflammatory Response after Moderate Contusion Spinal Cord Injury: A Time Study

Simple Summary The neuroinflammatory response is a rather complex event in spinal cord injury (SCI) and has the capacity to exacerbate cell damage but also to contribute to the repair of the injury. This complexity is thought to depend on a variety of inflammatory mediators, of which tumor necrosis factor (TNF) plays a key role. Evidence indicates that TNF can be both protective and detrimental in SCI. In the present study, we studied the temporal and cellular expression of TNF and its receptors after SCI in mice. We found TNF to be significantly increased in both the acute and the delayed phases after SCI, alongside a robust neuroinflammatory response. As we could verify some of our results in human postmortem tissue, our results imply that diminishing the detrimental immune signaling after SCI could also enhance recovery in humans. Spinal cord injury (SCI) initiates detrimental cellular and molecular events that lead to acute and delayed neuroinflammation. Understanding the role of the inflammatory response in SCI requires insight into the temporal and cellular synthesis of inflammatory mediators. We subjected C57BL/6J mice to SCI and investigated inflammatory reactions. We examined activation, recruitment, and polarization of microglia and infiltrating immune cells, focusing specifically on tumor necrosis factor (TNF) and its receptors TNFR1 and TNFR2. In the acute phase, TNF expression increased in glial cells and neuron-like cells, followed by infiltrating immune cells. TNFR1 and TNFR2 levels increased in the delayed phase and were found preferentially on neurons and glial cells, respectively. The acute phase was dominated by the infiltration of granulocytes and macrophages. Microglial/macrophage expression of Arg1 increased from 1-7 days after SCI, followed by an increase in Itgam, Cx3cr1, and P2ry12, which remained elevated throughout the study. By 21 and 28 days after SCI, the lesion core was populated by galectin-3(+), CD68(+), and CD11b(+) microglia/macrophages, surrounded by a glial scar consisting of GFAP(+) astrocytes. Findings were verified in postmortem tissue from individuals with SCI. Our findings support the consensus that future neuroprotective immunotherapies should aim to selectively neutralize detrimental immune signaling while sustaining pro-regenerative processes.