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Sepsis-associated encephalopathy (SAE) is a devastating neurological complication of sepsis with intolerable high motility. SAE is accompanied with brain vascular injury, endothelial hyperpermeability, and neutrophil infiltration into the brain tissue, key inflammatory processes leading to further brain edema and neuronal cell apoptosis. Recent studies from us and others suggest that the chemokine receptor C-X-C Motif Chemokine Receptor 2 (CXCR2) is crucial for neutrophil recruitment during SAE. Here we use CXCR2 antagonist SB225002 to characterize the role of CXCR2 in brain infiltration of neutrophil in a murine model of SAE. Systemic administration of high-dose LPS (10 mg/kg) induced evident neutrophil infiltration into the cerebral cortex in wild-type mice. However, CXCR2 antagonist SB225002 markedly attenuated neutrophil infiltration into brain. The CXCR2 expression on neutrophils in the peripheral circulation was dramatically downregulated in response to this LPS dose, and endothelial CXCR2 was significantly upregulated, suggesting endothelial but not neutrophil CXCR2 plays a more important role in neutrophil infiltration into brain. Strikingly, although these CXCR2 antagonist SB225002 treated mice displayed reduced neutrophil infiltration, no change in neutrophil rolling and adhesion was observed. Furthermore, we confirmed that CXCR2 agonist CXCL1 induced a marked increase in actin stress fiber synthesis and paracellular gap formation in cultured cerebral endothelial cells, which is attenuated by SB225002. Thus, these results demonstrate a selective role for endothelial CXCR2 to regulate cerebral vascular permeability and neutrophil transmigration in high-dose LPS induced neuroinflammation, and also suggest a therapeutic potential of CXCR2 antagonist SB225002 in SAE. • CXCR2 antagonist SB225002 markedly attenuated neutrophil infiltration into brain in systemic administration of high-dose LPS (10 mg/kg) induced neuroinflammation. • Although these CXCR2 antagonist SB225002 treated mice displayed reduced neutrophil infiltration, no change in neutrophil rolling and adhesion was observed. • CXCR2 activation by CXCL1 induced a marked increase in actin stress fiber synthesis and paracellular gap formation in cultured cerebral endothelial cells, which is attenuated by SB225002. [ABSTRACT FROM AUTHOR]

Abstract: Fingolimod (FTY720), an immunomodulator, is approved as an oral treatment for patients with relapsing forms of multiple sclerosis. Its effects are largely attributed to its mechanism of selectively retaining lymphocytes in the lymph nodes to reduce autoreactive T‐cell recruitment in the CNS. In this study, we investigated the therapeutic effect of FTY720 on an animal model of CNS inflammation induced by intracerebral ventricle LPS injection. We found that FTY720 treatment significantly prevented LPS‐induced neutrophil recruitment in the CNS by inhibiting leukocyte recruitment in cerebral microvessels. Furthermore, FTY720 also inhibited the expressions of adhesion molecules on the cerebral endothelium, but did not affect the expression levels of pro‐inflammatory cytokines (TNF‐α and IL‐6) and chemokines (CXCL1 and CXCL2) in the CNS parenchyma. The inhibition of endothelial activation was accompanied by reduced phosphorylation of signaling molecules, including serine/threonine‐specific protein kinase (Akt), STAT6, and nuclear factor‐κB. This FTY720‐attenuated inhibition of leukocyte recruitment and endothelial activation was reversed by blocking the functions of sphingosine kinase 2 or sphingosine‐1‐phosphate receptor 1. Our study demonstrated, for the first time, that FTY720 directly inhibits the phosphorylation of multiple signaling molecules in endothelial cells, thereby effectively blocking leukocyte recruitment in the CNS. [ABSTRACT FROM AUTHOR]