Therapeutic Advances and Immunoregulation Mechanisms of the Spleen in Traumatic Brain Injury

Traumatic Brain Injury (TBI) is a leading global cause of mortality and disability. Its pathophysiology encompasses two distinct phases: primary and secondary injury. The secondary injury phase, which involves complex mechanisms such as neuroinflammation, oxidative stress, and apoptosis, is a critical contributor to neurological deterioration. Traditionally, TBI has been considered an isolated event of the central nervous system (CNS), with therapeutic strategies focusing primarily on intracranial targets. However, recent research has revealed that TBI triggers a potent systemic immune and inflammatory response. The spleen, as the body's largest secondary lymphoid organ, plays a pivotal dual role in this process, acting as both an “amplifier” and a “regulator”. This narrative review aims to comprehensively elucidate the dual role of the spleen (pro-inflammatory and anti-inflammatory) in the pathological progression following TBI. It will provide an in-depth analysis of the regulatory mechanisms involving spleen-derived immune cells (particularly macrophages and T cells), inflammatory factors, and the signaling pathways of the “brain-spleen” axis (such as the cholinergic anti-inflammatory pathway, the sympathetic nervous pathway, and the HPA axis). Building on this foundation, this article will critically summarize recent advances in spleen-targeted therapeutic strategies, including splenectomy, pharmacological modulation of splenic function, neurostimulation to modulate the brain-spleen axis, and stem cell therapy. Furthermore, it will discuss the challenges associated with clinical translation and outline future directions, thereby providing a theoretical framework and novel perspectives for developing new immunomodulatory interventions for TBI.