Abstract
The blood–brain barrier (BBB) is key to establishing and maintaining homeostasis in the central nervous system (CNS); meningitis bacterial infection can disrupt the integrity of BBB by inducing an inflammatory response. The changes in the cerebral uptake of amino acids may contribute to inflammatory response during infection and were accompanied by high expression of amino acid transporters leading to increased amino acid uptake. However, it is unclear whether amino acid uptake is changed and how to affect inflammatory responses in mouse brain microvascular endothelial (bEnd.3) cells in response to Avian Pathogenic Escherichia coli TW-XM (APEC XM) infection. Here, we firstly found that APEC XM infection could induce serine (Ser) and glutamate (Glu) transport from extracellular into intracellular in bEnd.3 cells. Meanwhile, we also shown that the expression sodium-dependent neutral amino acid transporter 2 (SNAT2) for Ser and excitatory amino acid transporter 4 (EAAT4) for Glu was also significantly elevated during infection. Then, in amino acid deficiency or supplementation medium, we found that Ser or Glu transport were involving in increasing SNAT2 or EAAT4 expression, mTORC1 (mechanistic target of rapamycin complex 1) activation and inflammation, respectively. Of note, Ser or Glu transport were inhibited after SNAT2 silencing or EAAT4 silencing, resulting in inhibition of mTORC1 pathway activation, and inflammation compared with the APEC XM infection group. Moreover, pEGFP-SNAT2 overexpression and pEGFP-EAAT4 overexpression in bEnd.3 cells all could promote amino acid uptake, activation of the mTORC1 pathway and inflammation during infection. We further found mTORC1 silencing could inhibit inflammation, the expression of SNAT2 and EAAT4, and amino acid uptake. Taken together, our results demonstrated that APEC TW-XM infection can induce Ser or Glu uptake depending on amino acid transporters transportation, and then activate amino acid-mTORC1 pathway to induce inflammation in bEnd.3 cells.
Highlights
Bacterial meningitis is a serious brain disease that is associated with high morbidity and mortality [1,2]
We found that meningitis Avian Pathogenic Escherichia coli TW-XM (APEC XM) infection induced the transport of Ser and Glu from extracellular into intracellular depending on the transporters which activate the mTOR complex1 (mTORC1) pathway, and induce an inflammatory response in bEnd.3 cells
The results of this study showed that avian pathogenic E. coli (APEC) XM infection leads to an increase in the intracellular uptake of Ser and Glu in bEnd.3 cells, and a corresponding decrease in the extracellular content of two amino acids (Figure 1)
Summary
Bacterial meningitis is a serious brain disease that is associated with high morbidity and mortality [1,2]. BMECs normally regulate the transportation and absorption of nutrients to maintain the integrity of the BBB [11], they can produce a large number of pro-inflammatory factors when infected by meningitis bacteria, thereby enhancing the disruption of BBB integrity [12,13]. Inducible nitric oxide synthase (iNOS) was upregulated in endothelial cells resulting in disruption of the integrity of the BBB during infection [14]. A better understanding of the processes and mechanisms underlying BBB inflammation may contribute to the development of novel therapeutics against bacterial meningitis
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