Abstract
Stroke disrupts the homeostatic balance within the brain and is associated with a significant accumulation of necrotic cellular debris, fluid, and peripheral immune cells in the central nervous system (CNS). Additionally, cells, antigens, and other factors exit the brain into the periphery via damaged blood–brain barrier cells, glymphatic transport mechanisms, and lymphatic vessels, which dramatically influence the systemic immune response and lead to complex neuroimmune communication. As a result, the immunological response after stroke is a highly dynamic event that involves communication between multiple organ systems and cell types, with significant consequences on not only the initial stroke tissue injury but long-term recovery in the CNS. In this review, we discuss the complex immunological and physiological interactions that occur after stroke with a focus on how the peripheral immune system and CNS communicate to regulate post-stroke brain homeostasis. First, we discuss the post-stroke immune cascade across different contexts as well as homeostatic regulation within the brain. Then, we focus on the lymphatic vessels surrounding the brain and their ability to coordinate both immune response and fluid homeostasis within the brain after stroke. Finally, we discuss how therapeutic manipulation of peripheral systems may provide new mechanisms to treat stroke injury.
Highlights
Maintaining homeostasis is important during both steady-state conditions and disease for survival
Treatment with the vascular endothelial growth factor receptor (VEGFR)-3 inhibitor after EAE caused the regression of dural Meningeal lymphatic vessels (mLVs), while lymphatics near the cribriform plate (CP) remained unaffected after EAE [1]
This suggests that lymphatic vessels in the central nervous system (CNS) have heterogeneous roles and responses to vascular endothelial growth factor (VEGF)-C/VEGFR-3 signaling during steady-state and neuroinflammation
Summary
Maintaining homeostasis is important during both steady-state conditions and disease for survival. The central nervous system (CNS) has been characterized as an “immune-privileged” region, unlike peripheral organs, because it does not have conventional lymphatic vasculature, and barriers tightly limit the presence of peripheral immune cells [1,4,5,6,7]. Even though stroke can result in death and long-term disability with significant complications, there is only one FDA-approved drug, recombinant tissue plasminogen activator (rtPA), for ischemic stroke patients [15,16,17,18,19,20]. We briefly discuss dynamic immune responses across different contexts during the stroke and the function of lymphatic vessels surrounding the CNS during this process.
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