Title:Propofol Attenuates LPS-induced Inflammation by Suppressing the Activation of Histone Lactylation in hCMEC/D3 Cells
Volume: 22
Issue: 4
Author(s): Xiaowei Ding, Yaojun Lu, Jiawei Chen*Xiangyuan Chen*
Affiliation:
- Department of Anesthesiology, Jing’an District Central Hospital of Shanghai, Fudan University, No259 XiKang
Road, Shanghai, 200040, China
- Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong
University School of Medicine, Shanghai, 200080, China
Keywords:
Lipopolysaccharide, Propofol, hCMEC/D3 cells, lactylation, inflammation, ferroptosis.
Abstract:
Introduction: Neuroinflammation is recognized as one of the pathogenic mechanisms
underlying sepsis-associated encephalopathy (SAE). As the most commonly used anesthetic
agent in the perioperative period, propofol has been demonstrated to exhibit neuroprotective and
anti-inflammatory effects. This study aimed to investigate whether propofol could mitigate lipopolysaccharide
(LPS)-mediated neuroinflammation and to explore the potential mechanisms.
Methods: hCMEC/D3 cells were treated with propofol, followed by LPS exposure. Western
blot, ELISA, and RT-qPCR were used to assess the expression (both protein and mRNA levels)
of potential pathway participants. Intracellular Fe2+ levels were determined using an Iron Assay
Kit. In addition, an in vitro blood-brain barrier (BBB) model was constructed by co-culturing
hCMEC/D3 cells and human astrocytes, and BBB permeability was assessed by measuring
trans-endothelial electrical resistance (TEER).
Results: LPS (50 μg/mL, 1 h) significantly increased the secretion of TNF-α and IL-1β, induced
intracellular Fe2+ accumulation, and upregulated the expression of 4-HNE, H3K18la, pan-Kla,
and LDHA, while decreasing the expression of ZO-1, Claudin-5, and Occludin in hCMEC/D3
cells. More importantly, propofol (25 μM, 2 h) alleviated the aforementioned effects of LPS on
hCMEC/D3 cells. Furthermore, we observed significant LPS-induced TEER reduction in the in
vitro BBB model, and this effect was attenuated by propofol pretreatment.
Discussion: The protective effect of propofol on hCMEC/D3 cells' ferroptosis and LDHAlactylation
induced by LPS may be an important mechanism for neuroinflammation.
Conclusion: Propofol inhibits LPS-induced lactylation, ferroptosis, and release of inflammatory
cytokines in hCMEC/D3 cells by downregulating the expression of LDHA.
