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. Here we show that a brain-to-cervical lymph node (CLN) pathway is involved. 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. Microarray analyses of isolated lymphatic endothelium from CLNs of ischemic mice confirm the activation of transmembrane tyrosine kinase pathways. Blockade of VEGFR3 reduces lymphatic endothelial activation, decreases pro-inflammatory macrophages, and reduces brain infarction. In vitro, VEGF-C/VEGFR3 signalling in lymphatic endothelial cells enhances inflammatory responses in co-cultured macrophages. Lastly, surgical removal of CLNs in mice significantly reduces infarction after focal cerebral ischemia. These findings suggest that modulating the brain-to-CLN pathway may offer therapeutic opportunities to ameliorate systemic inflammation and brain injury after stroke.

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Background: Effect of Ninjurin1 deletion in the experimental autoimmune encephalomyelitis (EAE) mice has not been examined. Results: Ninjurin1 knock-out (KO) mice are resistance to EAE due to a defect of leukocyte recruitment into lesion sites. Conclusion: Ninjurin1 is a potent target molecule for treating inflammatory diseases such as multiple sclerosis. Significance: Our study proved contribution of Ninjurin1 in EAE pathogenesis in vivo and supports the importance of its targeting strategies.

Background and Purpose: The complexity and heterogeneity of stroke as well as the associated co-morbidities may render neuroprotective drugs less efficacious in clinical practice. Therefore, development of targeted therapies to specific patient subsets has become a high priority in translational stroke research. Ischemic stroke with type 2 diabetes (T2D) have a nearly double mortality rate and worse neurological outcomes. In the present study we tested our hypothesis that recombinant human fibroblast growth factor 21 (rFGF21) administration is beneficial for improving neurological outcomes of ischemic stroke with T2D. Methods: Type 2 diabetes db/db and non-diabetic genetic control db/+ mice were subjected into permanent focal ischemia of distal middle cerebral artery occlusion (dMCAO), we examined the effects of post stroke administration with rFGF21 in systemic metabolic disorders, inflammatory gatekeeper PPARγ activity at 3 days, mRNA expression of inflammatory cytokines and microglia/macrophage activation at 7 days in the peri-lesion cortex, and lastly neurological function deficits, ischemic brain infarction and white matter integrity up to 14 days after stroke of db/db mice. Results: After permanent focal ischemia, diabetic db/db mice presented confounding pathological features including metabolic dysregulation, more severe brain damage and neurological impairment, especially aggravated pro-inflammatory response and white matter integrity loss. However, daily rFGF21 treatment initiated at 6 hours after stroke for 14 days significantly normalized systemic metabolic disorders, rescued PPARγ activity decline, inhibited pro-inflammatory cytokine mRNA expression and M1-like microglia/macrophage activation in the brain. Importantly rFGF21 also significantly reduced white matter integrity loss, ischemic brain infarction, and neurological function deficits up to 14 days after stroke. The potential mechanisms of rFGF21 may in part consist of potent systematic metabolic regulation and PPARγ-activation promotion-associated anti-proinflammatory roles in the brain. Conclusions: Taken together, these results suggest rFGF21 might be a novel and potent candidate of the disease-modifying strategy for treating ischemic stroke with T2D.