Activation of the liver X receptor α protects the blood-brain barrier against heatstroke-induced injury.

Background: Impairment of blood-brain barrier (BBB) contributes significantly to neuroinflammation and central nervous system (CNS) dysfunction in heatstroke. Our previous study revealed activation of liver X receptor α (LXRα) alleviates the heat stress-induced proinflammatory response in CNS; however, whether this protective effect is mediated by maintaining BBB integrity remains unknown. In this study, we focused on BBB integrity to explore the underlying mechanisms of LXRα in heatstroke.

Methods: T0901317 (T0), an agonist of LXRα, was used to activate LXRα both in vivo and in vitro. Neurological deficits, neuroinflammation and BBB disruption were measured after mice were subjected to heatstroke. The BBB-mediated protective mechanism of LXRα activation in heatstroke was explored with brain microvascular endothelial cells in vitro.

Results: Administration of T0 immediately after the onset of heatstroke significantly ameliorated heatstroke-induced neuroinflammation and neurological deficits. In addition, BBB leakage caused by heatstroke was alleviated by T0, and this protective effect was achieved by enhancing tight junctions in brain microvascular endothelial cells. Mechanistically, we found that expression of ATP-binding cassette transporter A1 (ABCA1) was increased after LXRα activation, whereas ABCA1 knockdown using esiRNAs abolished LXRα activation-mediated BBB preservation by suppressing the Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) signaling pathway in brain microvascular endothelial cells.

Conclusions: Our results indicated that LXRα activation could alleviate neuroinflammation and CNS dysfunction in heatstroke by maintaining BBB integrity, and relevant mechanisms may be related to JAK2/STAT3 signal activation via ABCA1. This research provide a novel strategy for managing heatstroke-associated BBB dysfunction.