T cell receptor activation contributes to brain damage after intracerebral hemorrhage in mice.

BACKGROUND: Our previous studies demonstrated that activated T cells accumulate in perihematomal regions following intracerebral hemorrhage (ICH) and exacerbate hemorrhagic brain injury. In the present study, we aimed to explore the mechanisms underlying brain-infiltrating T cell activation and the associated pathophysiological effects in neurological outcomes following ICH. METHODS: We employed standardized collagenase injection-induced and autologous blood injection models of ICH in male C57BL/6J mice. T cell receptor (TCR) activation, immune cell infiltration, and cytokine production were quantified through immunostaining, flow cytometry, and cytokine arrays at 1- and 3-days post-ICH. Brain edema volume was measured at 3 days post-ICH and neurobehavioral assessments were conducted up to 14 days post-ICH. Pharmacological inhibition of TCR activation was achieved using the TCR-specific inhibitor AX-024, administered intraperitoneally at a dosage of 10 mg/kg 1-hour post-ICH. RESULTS: Flow cytometry and immunostaining detected TCR activation of brain-infiltrating T cells. Specific TCR activation inhibitor AX-024 administration markedly reduced TCR activation and the production of pro-inflammatory cytokines in the brain at 1- and 3-days post-ICH. Moreover, AX-024 administration led to a significant reduction in the infiltration of other leukocyte populations, and significantly reduced brain edema while improved long-term sensorimotor and cognitive outcomes up to 14 days post-ICH. DISCUSSION: Our findings underscore the critical role of TCR activation in the mobilization and activation of brain-infiltrating T cells post-ICH. Inhibition of TCR activation via AX-024 administration might be developed as a promising therapeutic strategy to improve neurological outcomes following ICH. However, further research is necessary to thoroughly explore the complex pathophysiological processes involved.