Infection with Japanese encephalitis virus (JEV) induces high morbidity and mortality, including potentially permanent neurological sequelae. However, the mechanisms by which viruses cross the blood-brain barrier (BBB) and invade into the central nervous system (CNS) remain unclear. Here, we show that extracellular HMGB1 facilitates immune cell transmigration. Furthermore, the migration of immune cells into the CNS dramatically increases during JEV infection which may enhance viral clearance, but paradoxically expedite the onset of Japanese encephalitis (JE). In this study, brain microvascular endothelial cells (BMECs) were utilized for the detection of HMGB1 release, and leucocyte, adhesion, and the integrity of the BBB in vitro. Genetically modified JEV-expressing EGFP (EGFP-JEV) and the BBB model were established to trace JEV-infected immune cell transmigration, which mimics the process of viral neuroinfection. We find that JEV causes HMGB1 release from BMECs while increasing adhesion molecules. Recombinant HMGB1 enhances leukocyte-endothelium adhesion, facilitating JEV-infected monocyte transmigration across endothelia. Thus, JEV successfully utilizes infected monocytes to spread into the brain, expanding inside of the brain, and leading to the acceleration of JE onset, which was facilitated by HMGB1. HMGB1-promoted monocyte transmigration may represent the mechanism of JEV neuroinvasion, revealing potential therapeutic targets.

Cancer patients usually suffer from unfavorable prognosis, particularly with the occurrence of brain metastasis of lung cancer. The key incident of brain metastasis initiation is crossing of blood-brain barrier (BBB) by cancer cells. Although preventing brain metastasis is a principal goal of cancer therapy, the cellular mechanisms and molecular regulators controlling the transmigration of cancer cells into the brain are still not clearly illustrated. We analyzed the mRNA expression profiles of metastatic brain tissues and TNF-α treated cancer cells to understand the changes in adhesion molecule expression during the tumor phase. To imitate the tumor microenvironment, an in vitro model was developed and the low or high metastatic potential lung tumor cells (A549 or H358) were cultured with the human brain microvascular endothelial cells (hBMECs) under TNF-α treatment. The analysis of online database indicated an altered expression for adhesion molecules and enrichment of their associated signaling pathways. TNF-α treatment activated hBMECs via up-regulating several adhesion molecules, including ICAM1, CD112, CD47, and JAM-C. Meanwhile, TNF-α induced an increased expression of adhesion molecule ligands such as ALCAM and CD6 in both A549 and H358. Moreover, the expression of adhesion molecules and the ligands were also increased both in A549- or H358-hBMECs mixed culture system, which promoted tumor cells adhesion to endothelial cells. These results suggested that the enhanced interaction between tumor cells and brain microvascular endothelium might facilitate the incidence of metastatic brain tumors and further offer a better comprehension of brain metastasis prevention and treatment.

The emergence of multidrug-resistant Pseudomonas aeruginosa infections has urged the need to find new strategies, such as the use of combinations of antibiotics. Among these, the combination of colistin with other antibiotics has been studied.

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