The skull bone marrow-meninges-brain axis: A new sentinel for neuroinflammation regulation in ischemic stroke

The central nervous system (CNS) has long been regarded as relatively immune-privileged, but the discovery of glymphatic transport and meningeal lymphatic vessels has reshaped our understanding of neuroimmune communication. In ischemic stroke, emerging evidence suggests that post-injury inflammation is regulated not only by systemic leukocyte recruitment and blood-brain barrier disruption but also by a spatially organized skull bone marrow-meninges-brain axis. Anatomical studies have identified vascular channels connecting calvarial bone marrow with the dura mater, providing a potential route for rapid communication between skull marrow immune niches and CNS border compartments. After ischemic injury, brain-derived inflammatory signals may activate adjacent skull marrow niches, while skull marrow-derived myeloid cells may migrate toward the meninges and contribute to early neuroinflammatory responses. In parallel, meningeal lymphatic vessels support the clearance of cerebrospinal fluid (CSF)-derived solutes, inflammatory mediators, antigens, and cellular debris toward deep cervical lymph nodes. This review integrates current evidence into a stage-dependent influx-efflux framework. In this model, skull-dura vascular channels may support local cellular influx and immune sensing, whereas meningeal lymphatic vessels provide a molecular and antigenic efflux pathway. The balance between these processes may influence edema formation, inflammatory amplification, immune resolution, and tissue repair after stroke. However, this axis remains an emerging concept rather than a fully established therapeutic target. Human evidence mainly supports anatomical plausibility and imaging accessibility, while direct demonstration of skull marrow-derived immune-cell trafficking in human stroke is still lacking. Further mechanistic, imaging, and translational studies are needed to determine whether this axis can guide precision monitoring and modulation of post-stroke neuroinflammation.