Abstract
Acute lung injury (ALI) is mainly caused by uncontrolled inflammatory response, and it remains without effective therapeutic options. 25‐hydroxycholesterol (25HC) has been reported to be a potent regulator of inflammation. The aim of this study was to investigate the effects of 25HC on lipopolysaccharide (LPS)‐induced ALI. C57BL/6 mice were pretreated with 25HC intraperitoneally before intratracheal exposure to LPS. Our results showed that 25HC pretreatment improved survival rate, attenuated the pathological changes of the lung and decreased the release of inflammatory cytokines in mice. Consistently, 25HC reduced expression of Toll‐like receptor (TLR4)‐mediated inflammatory cytokines in vitro. These effects of 25HC were obtained by preventing LPS binding to TLR4 via interaction with myeloid differentiation protein 2 (MD‐2). Crystal structure analysis suggested that 25HC could bind MD‐2 with high affinity into its hydrophobic pocket. Furthermore, LPS‐induced activation of Akt/NF‐κB pathway was partially down‐regulated by 25HC pretreatment. In summary, this study demonstrates that 25HC could inhibit the overwhelming inflammatory response through MD‐2 interaction, which suppresses Akt/NF‐κB signalling pathway. These findings suggest 25HC may be a promising candidate for ALI prevention.
Highlights
Acute lung injury (ALI) is recognized as refractory hypoxaemia, noncardiogenic oedema, decreased lung compliance and diffuse pulmonary infiltrates, which often result in respiratory failure.[1]
During the process of immune response, LPS triggers a series of protein interactions to form a TLR4 complex that includes LPS, LPS‐binding protein (LBP), CD14 and myeloid differentiation protein 2 (MD‐2).26 To further explore the molecular mechanism of the inhibitory action of 25HC on LPS‐induced TLR4 signalling, we investigated whether 25HC interfered with the interaction of LPS and TLR4 complex
We further reveal that the underlying anti‐inflammatory mechanism of 25HC is mainly based on prevention of LPS binding to TLR4‐MD‐2 complex by its engagement with the hydrophobic pocket of MD‐2, which impairs the activation of downstream Akt/nuclear factor (NF)‐κb signalling and dampens induction of inflammatory cytokines
Summary
Acute lung injury (ALI) is recognized as refractory hypoxaemia, noncardiogenic oedema, decreased lung compliance and diffuse pulmonary infiltrates, which often result in respiratory failure.[1]. Oxysterols, oxidized forms of cholesterol, participate in cholesterol homeostasis, immune response and pathogenesis of several diseases such as neurodegenerative diseases and atherosclerosis.16 25‐ hydroxycholesterol (25HC), one of the oxysterols, has recently garnered much attention as a potential regulator of innate immunity and inflammation.[17] Previous studies have demonstrated 25HC possesses antiviral effects against various viruses, including vesicular stomatitis virus (VSV), human immunodeficiency virus (HIV), Ebola virus (EBOV) and Zika virus (ZIKV) through inhibition of viral entry.[18,19,20] 25HC has been reported to mediate the activation of NF‐κB signalling to induce IL‐6 and IL‐8 expression.[21,22] A recent study observed that 25HC decreased the production of IL‐1β and inflammasome activity, leading to improve recovery from septic shock.[23] These findings suggested that 25HC could be involved in the regulation of inflammatory processes and its function varies based on biological conditions. Our study reveals 25HC to possess anti‐inflammatory role in both mouse and cell models, which collectively indicate 25HC as a potential therapeutic option for ALI and other acute inflammatory diseases
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