Cross-species comparisons between pigs and mice reveal conserved sex-specific intraspinal inflammatory responses after spinal cord injury

Objective: Therapeutic translation is challenging in spinal cord injury (SCI) and large animal models with high clinical relevance may accelerate therapeutic development. Pigs have important anatomical and physiological similarities to humans. Intraspinal inflammation mediates SCI pathophysiology. The purpose of this study was to evaluate the effect of sex on inflammation and outcomes in a pig thoracic contusion/compression SCI model.

Methods: Adult (gonad-intact) male and female Yucatan miniature swine were subjected to either SCI or sham (laminectomy-only) injury.

Results: SCI caused locomotor dysfunction (measured with the Porcine Thoracic Injury Behavior Score) with some recovery over 6 weeks and limited tissue sparing at 6 weeks with no difference between sexes. Immunohistological evaluations of spinal cord tissue at 2 days and 6 weeks post-injury revealed intraspinal microglia/macrophage (IBA-1, CD68) and lymphocyte responses (T-cells (CD3) and B-cells (CD79a)) consistent with observations in rodents and humans. Astrocyte (GFAP) immunoreactivity was observed within the lesion core at 6 weeks in contrast to observations in rodents. No differences were seen for astrocytes, microglia, macrophages, B-cells, and neutrophil infiltration between males and females. Intraspinal CD3 + T-cell counts and T-cell microclusters were significantly higher in females compared to males 6 weeks post-injury. Interestingly, we observed a similar significant increase in intraspinal CD3 + T-cell accumulation in female vs. male mice at 6 weeks post-thoracic contusion SCI.

Interpretation: Our observations indicate that sex is a potential biological variable for T-cell infiltration and may contribute to sex-based differences in SCI pathophysiology and recovery outcomes.