Function of Multidrug Resistance Transporters is Disrupted by Infection Mimics in Human Brain Endothelial Cells. Issue 2 (3rd April 2021)

• Record Type: Journal Article
• Authors: Eustaquio Do Imperio, Guinever; Lye, Phetcharawan; Bloise, Enrrico; Matthews, Stephen G.
• Is Part Of: Tissue barriers. Volume 9:Issue 2(2021)
• Publication Date: 2021-04-03
• Subjects: Infection mimics -- lps -- polyi:C -- ssRNA -- cytokines -- blood-brain barrier (BBB) -- hCMEC/D3 -- p-glycoprotein (P-gp/ABCB1) -- breast Cancer Resistance Protein (BCRP/ABCG2); Biological transport -- Periodicals; Tissues -- Periodicals; Biological Transport -- Periodicals; Tissues -- Periodicals; 571
• DOI: 10.1080/21688370.2020.1860616
• Languages: English
• ISSNs: 2168-8370

Abstract

ABSTRACT: P-glycoprotein ( P -gp/ ABCB1 ) and breast cancer resistance protein (BCRP/ ABCG2 ) modulate the distribution of drugs and toxins across the blood-brain barrier (BBB). Animal studies reported that infection-induced disruption of these transporters in the developing BBB impairs fetal brain protection. However, the impact of infection mimics on P -gp/BCRP function in human brain endothelium is less well understood. We hypothesized that Toll-like receptor ligands mimicking bacterial and viral infection would modify the expression and function of P -gp and BCRP in human brain endothelial cells (BECs). Human cerebral microvascular endothelial cells (hCMEC/D3) were challenged with bacterial [Lipopolysaccharide (LPS)] and viral-mimics [polyinosinic:polycytidylic acid (PolyI:C) or single-stranded RNA (ssRNA)], or pro-inflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α and interferon gamma (IFN)-ɣ. P -gp and BCRP function was assessed after 4 or 24 h, using Calcein-AM and Chlorin-6 assays, respectively. Western blot and qPCR quantified P -gp/ ABCB1 and BCRP/ ABCG2 expression following treatments. Infection mimics are potent modulators of drug transporters in human BECs in vitro . LPS and PolyI:C increased, while ssRNA exposure reduced P -gp activity. In contrast, LPS and PolyI:C decreased, while ssRNA increased BCRP activity ( P < .05). There was little correlation between drug transporter function, gene expression and total protein level. Altered plasma membrane BCRP may suggest modified intracellular trafficking induced by infection in human BECs. Bacterial and viral infection mimics modify P -gp and BCRP transport function in human BECs, in vitro . This knowledge may contribute and have important implications for human brain protection and possible altered biodistribution of drugs and xenobiotics in the brain following exposure to TLR agonists.