Andy
Senior Member (Voting rights)
Abstract
The central nervous system is surrounded by three interconnected membranes referred to as the meninges, which host a diverse immune network1,2,3. Within the skull-interfacing dura mater are venous sinuses, large veins that are traditionally viewed as passive blood drains for the brain and skull4,5. However, these structures also constitute an important neuroimmune interface6,7,8. Here we used intravital microscopy to gain mechanistic insight into this interface and reveal that dural sinuses and their endothelial cells form a highly dynamic surface that continually restructures to regulate blood flow, fluid movement and immune surveillance.
We show that sinuses are not passive conduits, but instead undergo RAMP1-dependent constriction and dilation mediated by smooth muscle, resembling arterial behaviour. Moreover, the superior sagittal sinus in mice is bifurcated into upper and lower chambers that contribute to intracranial pressure regulation. Both chambers are lined by specialized, highly fenestrated sinus endothelial cells (SECs) that permit movement of fluids, macromolecules and microorganisms between the sinus lumen and leukocyte-rich perisinus space. To safeguard this permeable interface, SECs dynamically open and close intercellular boundaries in a RAMP2-dependent manner. Transcranial RAMP2 antagonism impaired SEC boundary dynamics and reduced immune cell trafficking along the sinus wall during homeostasis and systemic viral infection. Disruption of SEC dynamics during infection compromised local antiviral immunity and promoted pathogen entry into the meninges. Together, these findings establish dural sinuses as dynamic venous structures that regulate fluid exchange and support immune surveillance and antiviral defence.
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The central nervous system is surrounded by three interconnected membranes referred to as the meninges, which host a diverse immune network1,2,3. Within the skull-interfacing dura mater are venous sinuses, large veins that are traditionally viewed as passive blood drains for the brain and skull4,5. However, these structures also constitute an important neuroimmune interface6,7,8. Here we used intravital microscopy to gain mechanistic insight into this interface and reveal that dural sinuses and their endothelial cells form a highly dynamic surface that continually restructures to regulate blood flow, fluid movement and immune surveillance.
We show that sinuses are not passive conduits, but instead undergo RAMP1-dependent constriction and dilation mediated by smooth muscle, resembling arterial behaviour. Moreover, the superior sagittal sinus in mice is bifurcated into upper and lower chambers that contribute to intracranial pressure regulation. Both chambers are lined by specialized, highly fenestrated sinus endothelial cells (SECs) that permit movement of fluids, macromolecules and microorganisms between the sinus lumen and leukocyte-rich perisinus space. To safeguard this permeable interface, SECs dynamically open and close intercellular boundaries in a RAMP2-dependent manner. Transcranial RAMP2 antagonism impaired SEC boundary dynamics and reduced immune cell trafficking along the sinus wall during homeostasis and systemic viral infection. Disruption of SEC dynamics during infection compromised local antiviral immunity and promoted pathogen entry into the meninges. Together, these findings establish dural sinuses as dynamic venous structures that regulate fluid exchange and support immune surveillance and antiviral defence.
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Probably limited time access