![]() ![]() ![]() In SD rats, injection of Evans blue into the lateral ventricles or brain parenchyma led to the rapid appearance of the dye in CLNs dye-derived fluorescence was not detectable in axillary lymph nodes (ALNs) or inguinal lymph nodes (ILNs) (Fig. Further molecular dissection of this pathway may lead to novel therapeutic approaches for ischemic stroke. These data suggest that brain-to-CLN signaling may be responsible for triggering systemic inflammatory responses after acute stroke. In this proof-of-concept study, we use rat and mouse models of focal cerebral ischemia along with co-cultures of lymphatic endothelium and macrophages to show that (a) VEGF-C/VEGFR3 signaling activates lymphatic endothelium in CLNs after ischemic stroke, and (b) pharmacological blockade of VEGFR3 signaling or surgical removal of superficial CLNs ameliorates post-stroke inflammation and reduces brain injury. The CNS drainage into lymph nodes may be involved in tissue inflammation since it has been reported that excision of the CNS-draining lymph nodes reduced the pathology of experimental autoimmune encephalomyelitis within the spinal cord 28. Lymphatic-like structures in meninges were described in adult mouse brains and this pathway may carry extracellular solutes into cervical nodes 25, 26, 27. In rabbits and sheep, these lymphatic-like systems absorbed 30–50% of total outflow, while the rest might be drained through arachnoid villi 20, 21.ĭrainage from CNS into cervical lymph nodes (CLNs) has been documented in multiple studies utilizing tracers or antigen injection into CSF 22, 23, 24. ![]() More recently, extensive studies in many different species have indicated a role for additional routes for CSF drainage, whereby CSF, interstitial fluid (ISF), cells, and soluble antigen drain from the subarachnoid space to the cribriform plate and nasal mucosa in animals and humans 16, 17, 18, 19. Historically, arachnoid villi in the superior sagittal sinus are known as outflow sites for absorption of the CSF into the blood stream 13, 14, 15. However, what remains unknown is how the damaged brain sends the initial signal to trigger peripheral responses in the first place.Ĭerebrospinal fluid (CSF) is produced by the choroid plexus and flows through ventricles to reach the subarachnoid space and dural venous sinuses 11, 12. In general, infiltrated immune cells contribute to secondary injury but it is now recognized that both negative and positive effects may take place. ![]() After stroke, leukocytosis is associated with stroke severity, infarct volume, and worse functional outcomes 7, 8, 9, whereas, under some circumstances, monocyte-derived macrophages can mediate phagocytosis for clean-up and tissue remodeling during the recovery phase after stroke 10. These inflammatory signals in the periphery are then thought to regulate the complex immune response in the CNS. For example, release of cytokines such as IL-6 and TNF-alpha from peripheral blood cells were increased in patients after stroke 6. After CNS injury or disease, peripheral circulating immune cells are rapidly activated, cross the blood brain barrier, and influence injury and recovery 3, 4, 5. Multifactorial signals can be produced by damaged brain cells and these may act as chemoattractants and activators of granulocytes, macrophages, and other inflammatory cells 1, 2. Inflammation after stroke is highly complex. These findings suggest that modulating the brain-to-CLN pathway may offer therapeutic opportunities to ameliorate systemic inflammation and brain injury after stroke. Lastly, surgical removal of CLNs in mice significantly reduces infarction after focal cerebral ischemia. In vitro, VEGF-C/VEGFR3 signalling in lymphatic endothelial cells enhances inflammatory responses in co-cultured macrophages. Blockade of VEGFR3 reduces lymphatic endothelial activation, decreases pro-inflammatory macrophages, and reduces brain infarction. Microarray analyses of isolated lymphatic endothelium from CLNs of ischemic mice confirm the activation of transmembrane tyrosine kinase pathways. In rats subjected to focal cerebral ischemia, lymphatic endothelial cells proliferate and macrophages are rapidly activated in CLNs within 24 h, in part via VEGF-C/VEGFR3 signalling. Here we show that a brain-to-cervical lymph node (CLN) pathway is involved. After stroke, peripheral immune cells are activated and these systemic responses may amplify brain damage, but how the injured brain sends out signals to trigger systemic inflammation remains unclear. ![]()
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