Highly dynamic dural sinuses support meningeal immunity 2308983

Abstract

Abstract Introduction The central nervous system is surrounded by three interconnected meningeal membranes, including the dura mater, which contains venous sinuses traditionally viewed as passive drains for blood and cerebral spinal fluid. Because the sinuses collect fluid and cellular traffic from the brain and skull, they are also major sites of innate and adaptive immune surveillance. However, it is unclear how the endothelial cells comprising these sinuses sense and respond to changing fluid forces and immune cues to support steady-state immune surveillance and effective protection against infection. Methods We used intravital, light-sheet, and confocal microscopy, complemented by genomic analyses and pharmacological perturbations, to examine sinus structure, sinus endothelial cell (SEC) behavior, fluid transport, and immune activity. Results We found that the dural sinuses and SECs are highly dynamic surfaces that continually restructure to modulate fluid movement and immune surveillance. The murine sagittal sinus is a bifurcated structure that regulates fluid movement through smooth muscle-dependent vasomotion. SECs further support fluid movement by forming transient micron-sized openings within and between cells. Sinus porosity increased with VEGFA treatment and in the absence of meningeal lymphatics. These openings enabled macromolecules and microbes to move between the sinus lumen and leukocyte-rich perisinus space. Genomic and pharmacologic studies revealed that SEC boundary dynamics depend on RAMP2 signaling. Transcranial RAMP2 antagonism impeded SEC junctional activity, reduced immune cell movement along the sinus wall, and impaired local antiviral immunity after systemic infection. Conclusion These findings demonstrate that dural sinuses are highly dynamic neuroimmune interfaces. Specialized SECs regulate fluid transport and barrier permeability while coordinating steady-state immune surveillance and mounting effective antiviral immunity through continuous structural remodeling. Funding Source This work was supported by the intramural program at the National Institute of Neurological Disorders & Stroke (NINDS) within the National Institutes of Health (NIH). Topic Categories Neuroimmunology (NEUR)