Deletion of inflammasome adaptor protein ASC enhances functional recovery after spinal cord injury in mice.

BACKGROUND

Research has revealed the crucial roles of inflammasomes in various central nervous system disorders. However, the role of inflammasomes in secondary damage following spinal cord injury (SCI) remains incompletely understood.

METHODS

Here, we investigated the role of apoptosis-associated speck-like protein (ASC), an adaptor protein for inflammasome formation, after contusion SCI in ASC homozygous knockout (ASC) mice. Contusion SCI was induced using a force of 60 kdyn, and recovery of open-field locomotor performance was evaluated using the nine-point Basso Mouse Scale (BMS). Bone marrow transplantation (BMT) was performed to create mice chimeric for ASC expression in bone marrow cells.

RESULTS

Western blot analysis revealed that protein expression of NLRP3, ASC, Caspase-1, and IL-β were increased in injured spinal cords compared with sham-control spinal cords at 1 day post injury (dpi). Double immunostaining showed that ASC expression was co-localized to cellular constituents of the spinal cord, including NeuN neurons, CD11b microglia/macrophages, GFAP astrocytes, and MOG oligodendrocytes. ASC mice had significantly better locomotor function assessed by BMS than wild-type (WT) mice. ASC mice also had significantly reduced levels of Nlrp3, Casp1, IL1b, Il-6, Tnfa, Cxcl1, and Ly6g mRNA compared with WT mice. BMT (WT→ASC) mice had significantly better BMS scores than BMT (WT→WT) mice. BMT (ASC→WT) mice also had significantly better BMS scores than BMT (WT→WT) mice. However, the statistical significance was limited to time points between 7 and 21 dpi.

CONCLUSIONS

These results suggest that ASC-dependent inflammasome formation, especially in resident cells of the spinal cord, plays a pivotal role in the progression of secondary damage following SCI.