IL‐12p40 promotes secondary damage and functional impairment after spinal cord contusional injury

Abstract

Secondary damage obstructs functional recovery for individuals who have sustained a spinal cord injury (SCI). Two processes significantly contributing to tissue damage after trauma are spinal cord hemorrhage and inflammation: more specifically, the recruitment and activation of immune cells, frequently driven by pro‐inflammatory factors. Cytokines are inflammatory mediators capable of modulating the immune response. While cytokines are necessary to elicit inflammation for proper healing, excessive inflammation can result in destructive processes. The pro‐inflammatory cytokines IL‐12 and IL‐23 are pathogenic in multiple autoimmune diseases. The cytokine subunit IL‐12p40 is necessary to form bioactive IL‐12 and IL‐23. In this study, we examined the relationship between spinal cord hemorrhage and IL‐12‐related factors, as well as the impact of IL‐12p40 (IL‐12/IL‐23) on secondary damage and functional recovery after SCI. Using in vivo magnetic resonance imaging and protein tissue analyses, we demonstrated a positive correlation between IL‐12 and tissue hemorrhage. Receptor and ligand subunits of IL‐12 were significantly upregulated after injury and colocalized with astrocytes, demonstrating a myriad of opportunities for IL‐12 to induce an inflammatory response. IL‐12p40−/− mice demonstrated significantly improved functional recovery and reduced lesion sizes compared to wild‐type mice. Targeted gene array analysis in wild‐type and IL‐12p40−/− female mice after SCI revealed an upregulation of genes associated with worsened recovery after SCI. Taken together, our data reveal a pathogenic role of IL‐12p40 in the secondary damage after SCI, hindering functional recovery. IL‐12p40 (IL‐12/IL‐23) is thus an enticing neuroinflammatory target for further study as a potential therapeutic target to benefit recovery in acute SCI.

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“…Most prevalently after SCI, macrophages and microglia become activated after exposure to pro-inflammatory mediators, such as interferon-gamma (IFN-γ), tumor necrosis factoralpha (TNF-α), or lipopolysaccharide (LPS) [34], and exhibit a phenotype that results in pro-inflammatory cytokine secretion, phagocytosis, and collateral damage [35]. Microglia/macrophages and astrocytes secrete high levels of pro-inflammatory interleukin (IL)-12, IL-23, IL-1β, TNF-α, and IL-6, and low levels of anti-inflammatory IL-10, IL-4, and IL-13 [36][37][38], which cause further damage to vulnerable neural tissue. An excessive and dysfunctional increase in pro-inflammatory cytokines, interferons, and prostaglandins in acute SCI contributes to a cyclical influx of inflammatory cells and injury exacerbation at later injury stages.…”