CD44-mediated meningeal monocyte activity enhances immune surveillance in the central nervous system after traumatic brain injury

Traumatic brain injury triggers a complex immune response that plays a dual role in central nervous system recovery and neuroinflammation. Among various immune regulators, CD44–a cell surface adhesion molecule–has been implicated in traumatic brain injury pathology, but its precise functional role remains to be elucidated. In the present study, we demonstrated that CD44 expression is upregulated in the meninges following traumatic brain injury and that it plays a central role in orchestrating monocyte recruitment and activation within this compartment. Using a controlled cortical impact mouse model, we combined transcriptomic profiling with flow cytometry, western blotting, and immunohistochemistry analyses to identify a distinct immune signature characterized by increased meningeal monocyte infiltration and exacerbated neuroinflammation. Genetic knockdown of CD44 markedly altered this trajectory: it reduced monocyte-mediated inflammation, suppressed neuronal apoptosis, and significantly improved behavioral recovery. These findings identify CD44 as a critical mediator linking meningeal immune cell dynamics to post-traumatic neuroinflammatory processes. Thus, targeting CD44 may be a promising therapeutic strategy to modulate immune surveillance and promote neural repair following traumatic brain injury.