Highly dynamic dural sinuses support meningeal immunity
The central nervous system (CNS) is surrounded by three interconnected membranes referred to as the meninges, which host a diverse immune network1-3. Situated within the skull-interfacing dura mater are venous sinuses, which are large veins thought to serve predominantly as passive blood drains for the brain and skull4,5. However, these structures also represent an important neuroimmune interface6-8. Here, we sought mechanistic insights into this interface using intravital microscopy, revealing that the dural sinuses and associated endothelial cells are a highly dynamic surface that constantly restructures to modulate blood flow, fluid movement, and immune surveillance. Specifically, we demonstrate that sinuses are not passive drains but instead constrict and dilate under RAMP1-dependent smooth muscle control similar to arteries. In addition, the murine superior sagittal sinus is bifurcated into an upper and lower chamber, both comprised of specialized, highly fenestrated endothelial cells that allow the movement of fluids, macromolecules, and microbes between the sinus lumen and leukocyte-rich perisinus space. To protect this permeable interface, sinus endothelial cells (SECs) continually open and close their boundaries in a RAMP2-dependent manner. Transcranial RAMP2 antagonism impeded SEC boundary dynamics and immune cell movement along the sinus wall during steady state and after systemic viral infection. Interference with SEC dynamics during viral infection disrupted local antiviral immunity and facilitated pathogen entry into the meninges. These findings demonstrate that dural sinuses are dynamic venous drains with specialized SECs designed to control fluid movement and support both steady state immune surveillance and antiviral immunity. Overall design: Pooled cells representing lower sagittal sinus ("SINUS") and rostral-rhinal hub ("HUB") in mouse were prepared for single cell RNA sequencing and sequenced to an average of 35,000 reads per cell.