Sex Influences Penumbral Leukocyte Mobilization after Severe TBI

Post-traumatic brain injury (TBI) outcomes demonstrate sex-related heterogeneity, as some but not all reports favor females. Little is known about the mechanism responsible for post-TBI outcome sexual dimorphism nor how it relates to postinjury neuroinflammation. We hypothesized that post-TBI penumbral blood-brain barrier (BBB) leukocyte mobilization and microvascular permeability differ between sexes.

Female (F) (n = 12) and male (M) (n = 12) CD1 mice were randomized to controlled cortical impact (severe TBI) or sham craniectomy (Sh) using a validated murine model of TBI and tibial fracture. At 48 h, the four groups (female TBI [FTBI], male TBI [MTBI], female sham [FSh], and male sham [MSh] underwent in vivo pial intravital microscopy (IVM) visualizing live penumbral BBB leukocyte (LEU)-endothelial cell (EC) interactions and albumin leakage. Neuroclinical recovery was assessed by the Garcia Neurological Test (GNT), and the injured brain was procured for edema analysis (wet to dry).

Compared with Sh, only MTBI demonstrated significantly greater brain water at 48 h. Also, MTBI but not FTBI (FTBI: 15.7 ± 0.2 vs. FSh: 15.8 ± 0.2, p = 1.0) manifested worse GNT scores (MTBI: 15.0 ± 0.2 vs. MSh: 16.0 ± 0.0, p < 0.01). In vivo LEU rolling was significantly increased after TBI only in males, not females. Fluorescein isothiocyanate (FITC) BBB leakage was only significantly increased in injured males (MTBI: 0.43 ± 0.05 vs. MSh: 0.14 ± 0.03, p < 0.001; FTBI: 0.34 ± 0.04 vs. FSh: 0.19 ± 0.04, p = 0.08).

After severe TBI, only male mice manifest greater penumbral LEU mobilization and microvascular permeability. Injured males also demonstrate worse neuroclinical recovery and persistent brain edema. Sex-related differences in TBI outcomes may be related to penumbral-leukocyte-mediated injury and microvascular permeability.