Recombinant human DNase treatment mitigates extracellular trap mediated damage and improves long-term recovery after spinal cord injury in male mice

Abstract

After traumatic spinal cord injury (SCI), inflammation and other reactive processes exacerbate tissue damage and impair long-term motor recovery. Extracellular traps (ETs) are an immune cell effector function first described in neutrophils wherein chromatin is decondensed, decorated with cytotoxic granule enzymes, and expelled from the cell body. Recently, ETs have been linked to poor functional outcomes in SCI; however, translatable agents to prevent ET-mediated damage after SCI have yet to be explored. We assessed recombinant human (rh) DNase (trade name Pulmozyme) as a potential therapeutic that could be repurposed to break down ETs after SCI. To determine the timing of treatment, we characterized the timeline of ET formation in a thoracic contusion model of SCI in mice. We found that ETs levels increased in the injured spinal cord by 4 h post injury (hpi), peaking within 24 hpi. When rhDNase was administered at 1 hpi, DNase activity in the serum remained elevated for 24 hpi with a corresponding increase in circulating ET fragments. At 6 hpi, blood-spinal cord barrier permeability was attenuated in rhDNase-treated animals. Long-term functional hind limb recovery, as assessed by the ladder rung walking test, was improved at 35 dpi in rhDNase-treated animals compared to vehicle-treated controls. RhDNase-treated animals also exhibited shorter SCI lesion lengths at 35 dpi. Altogether, our data demonstrate the potential of rhDNase as an anti-ET therapeutic to improve long-term SCI outcomes.