25‐Hydroxycholesterol protects against acute lung injury via targeting MD‐2

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.

Exogenous Addition of 25‐Hydroxycholesterol Reduces Level of Very Long‐Chain Fatty Acids in X‐Linked Adrenoleukodystrophy

“…[13][14][15][16] In addition, 25-HC significantly reduced LPSinduced inflammatory response through interaction with myeloid differentiation protein 2. [17] In this study, we have undertaken further investigation on the pathophysiological role of 25-HC in X-ALD and revealed significant reduction of VLCFA (C26:0) by exogenous addition of 25-HC.…”

“…It also has been demonstrated that 25‐HC acts as an intrinsic lipid effector of the interferon antiviral response and suppresses viral infection for a broad range of viruses including zika virus . In addition, 25‐HC significantly reduced LPS‐induced inflammatory response through interaction with myeloid differentiation protein 2 …”

Porcine Reproductive and Respiratory Syndrome Virus E Protein Degrades Porcine Cholesterol 25-Hydroxylase via the Ubiquitin-Proteasome Pathway

“…Knockdown of pCH25H enhances E protein-mediated inflammatory responses. In addition to its antiviral activity, recent studies have suggested that 25HC, the metabolic product of CH25H, also regulates inflammatory cytokine production in vitro and in vivo (40,41). Coincidentally, PRRSV E protein has been demonstrated to induce inflammatory cytokine production (42,43), which is potentially associated with the PRRSV-induced inflammatory cytokine storm that occurs in late stages of virus infection.…”

“…Thus, we further investigated the potential relationship between pCH25H and PRRSV E protein-mediated inflammatory responses. Considering that conflicting results have been reported for the effects of 25HC on inflammatory responses (40,41,44,45), possible reasons for these discrepancies may be that different cell types and/or different concentrations of 25HC were used in the studies. Thus, we first evaluated the inflammatory cytokine expression of 3D4/21 cells after treatment with different concentrations of 25HC.…”

“…Consistent with these in vitro results, CH25H-deficient mice overproduced IL-1␣, IL-1␤, and IL-8 following lipopolysaccharide (LPS) injection and died more rapidly from septic shock (58). Ouyang et al showed that mice pretreated intraperitoneally with 25HC had attenuated LPS-induced inflammatory cytokine release and acute lung injury; these effects were mediated by interaction of 25HC with myeloid differentiation protein 2 (MD-2) and suppression of the Akt/NF᎑B signaling pathway (41). These studies support the repressive action of CH25H/25HC on inflammatory responses.…”