Traumatic spinal cord injury (SCI) is a relatively frequent event that imposes a massive burden on the health, quality of life and socioeconomic situation of affected persons. Tissue damage after SCI occurs in two phases: primary and secondary damage. Primary damage refers to the initial mechanical trauma causing cell death and tissue disruption while secondary damage includes multiple processes that can promote further damage. One critical secondary process is inflammation or the recruitment and activation of immune cells.

A more complete understanding of individual contributors to inflammatory damage is necessary to specifically target and modify detrimental factors. Inflammation after SCI is exacerbated, with activated microglia and monocyte-derived macrophages being the main immune cell populations in the injured tissue.

Pro-inflammatory cytokines IL-12 and IL-23 share the p40 subunit which is strongly upregulated after phagocytosis of red blood cells. IL-12 and IL-23 can be expressed by a multitude of cell types and mediate multiple functions on different target cells. 

Here, we assess the functional effect of IL-12 and IL-23 via IL-12p40 on SCI, using a low thoracic moderate contusion injury in mice.

First, we quantified protein expression using Western blot to find IL-12 factors upregulated compared to laminectomy controls. Furthermore, we observed a concurrent upregulation of IL-12p70 with hemoglobin, a biomarker for magnetic resonance imaging (MRI) spinal cord hemorrhage. We have identified IL-12p40 to be expressed primarily by astrocytes early after injury and by microglia by 28 days after injury. Both receptors IL12RB1 and IL12RB2 are robustly expressed in astrocytes.

To test the functional impact of IL-12 and IL-23 on SCI, we utilized IL-12p40 knockout mice and wildtype controls to quantify locomotor recovery after SCI using the Basso Mouse Scale (BMS). We observed improved recovery in IL-12p40 deficient mice compared to wildtype mice. IL-12p40 KO mice also demonstrate significantly more spared tissue 28 days after injury.

In summary, these results suggest that the absence of IL-12p40, but not IL-23p19, mediates a neuroprotective effect after contusion SCI, serving as a new potential therapeutic target to ameliorate secondary damage and promote better functional recovery outcomes.

Keywords: hemorrhage, astrocytes, neuroinflammation