Pregnane X Receptor Activation in Liver Macrophages Protects against Endotoxin-Induced Liver Injury,Advanced Science

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Pregnane X Receptor Activation in Liver Macrophages Protects against Endotoxin-Induced Liver Injury
Advanced Science ( IF 14.3 ) Pub Date : 2024-03-13 , DOI: 10.1002/advs.202308771
Tingting Zhao _{1,

2} , Guoping Zhong _{1,

2} , Ying Wang ₃ , Renjie Cao _{1,

2} , Shaofei Song _{1,

2} , Yuan Li _{1,

2} , Guohui Wan _{1,

2} , Haiyan Sun ₄ , Min Huang _{1,

2} , Huichang Bi ₅ , Yiming Jiang _{1,

2}

Affiliation

Endotoxemia-related acute liver injury has a poor prognosis and high mortality, and macrophage polarization plays a central role in the pathological process. Pregnane X receptor (PXR) serves as a nuclear receptor and xenosensor, safeguarding the liver from toxic stimuli. However, the effect and underlying mechanism of PXR activation on endotoxemic liver injury remain largely unknown. Here, the expression of PXR is reported in human and murine macrophages, and PXR activation modified immunotypes of macrophages. Moreover, PXR activation significantly attenuated endotoxemic liver injury and promoted macrophage M2 polarization. Macrophage depletion by GdCl₃ confirmed the essential of macrophages in the beneficial effects observed with PXR activation. The role of PXR in macrophages is further validated using AAV8-F4/80-Pxr shRNA-treated mice; the PXR-mediated hepatoprotection is impaired, and M2 polarization enhancement is blunted. Additionally, treatment with PXR agonists inhibited lipopolysaccharide (LPS)-induced M1 polarization and favored M2 polarization in BMDM, Raw264.7, and THP-1 cells. Further analyses revealed an interaction between PXR and p-STAT6 in vivo and in vitro. Moreover, blocking Pxr or Stat6 abolished the PXR-induced polarization shift. Collectively, macrophage PXR activation attenuated endotoxin-induced liver injury and regulated macrophage polarization through the STAT6 signaling pathway, which provided a potential therapeutic target for managing endotoxemic liver injury.

中文翻译：

肝脏巨噬细胞中的孕烷 X 受体激活可预防内毒素引起的肝损伤

内毒素血症相关的急性肝损伤预后差、死亡率高，巨噬细胞极化在病理过程中起核心作用。孕烷 X 受体 (PXR) 充当核受体和异种传感器，保护肝脏免受有毒刺激。然而，PXR 激活对内毒素血症性肝损伤的影响和潜在机制仍不清楚。在此，报道了 PXR 在人和鼠巨噬细胞中的表达，并且 PXR 激活改变了巨噬细胞的免疫类型。此外，PXR 激活显着减轻内毒素血症性肝损伤并促进巨噬细胞 M2 极化。 GdCl ₃消耗巨噬细胞证实了巨噬细胞在 PXR 激活所观察到的有益作用中的重要性。使用 AAV8- F4/80 - Pxr shRNA 处理的小鼠进一步验证了 PXR 在巨噬细胞中的作用； PXR 介导的肝脏保护功能受损，M2 极化增强减弱。此外，在 BMDM、Raw264.7 和 THP-1 细胞中，使用 PXR 激动剂处理可抑制脂多糖 (LPS) 诱导的 M1 极化，并有利于 M2 极化。进一步的分析揭示了 PXR 和 p-STAT6 在体内和体外的相互作用。此外，阻断Pxr或Stat6消除了 PXR 引起的偏振偏移。总的来说，巨噬细胞 PXR 激活减轻了内毒素引起的肝损伤，并通过 STAT6 信号通路调节巨噬细胞极化，这为治疗内毒素性肝损伤提供了潜在的治疗靶点。

更新日期：2024-03-13

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