Background Inflammation-exacerbated secondary brain injury and limited tissue regeneration are barriers to favourable prognosis after intracerebral haemorrhage (ICH). As a regulator of inflammation and lipid metabolism, Liver X receptor (LXR) has the potential to alter microglia/macrophage (M/M) phenotype, and assist tissue repair by promoting cholesterol efflux and recycling from phagocytes. To support potential clinical translation, the benefits of enhanced LXR signalling are examined in experimental ICH. Methods Collagenase-induced ICH mice were treated with the LXR agonist GW3965 or vehicle. Behavioural tests were conducted at multiple time points. Lesion and haematoma volume, and other brain parameters were assessed using multimodal MRI with T2-weighted, diffusion tensor imaging and dynamic contrast-enhanced MRI sequences. The fixed brain cryosections were stained and confocal microscopy was applied to detect LXR downstream genes, M/M phenotype, lipid/cholesterol-laden phagocytes, oligodendrocyte lineage cells and neural stem cells. Western blot and real-time qPCR were also used. CX3CR1CreER: Rosa26iDTR mice were employed for M/M-depletion experiments. Results GW3965 treatment reduced lesion volume and white matter injury, and promoted haematoma clearance. Treated mice upregulated LXR downstream genes including ABCA1 and Apolipoprotein E, and had reduced density of M/M that apparently shifted from proinflammatory interleukin-1β+ to Arginase1+CD206+ regulatory phenotype. Fewer cholesterol crystal or myelin debris-laden phagocytes were observed in GW3965 mice. LXR activation increased the number of Olig2+PDGFRα+ precursors and Olig2+CC1+ mature oligodendrocytes in perihaematomal regions, and elevated SOX2+ or nestin+ neural stem cells in lesion and subventricular zone. MRI results supported better lesion recovery by GW3965, and this was corroborated by return to pre-ICH values of functional rotarod activity. The therapeutic effects of GW3965 were abrogated by M/M depletion in CX3CR1CreER: Rosa26iDTR mice. Conclusions LXR agonism using GW3965 reduced brain injury, promoted beneficial properties of M/M and facilitated tissue repair correspondent with enhanced cholesterol recycling. Data are available on reasonable request. The data that support the findings of this study are available from the corresponding authors on reasonable request.

中文翻译：

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增强的肝脏 X 受体信号传导可减少实验性脑出血后的脑损伤并促进组织再生：小胶质细胞/巨噬细胞的作用

背景 炎症加剧的继发性脑损伤和有限的组织再生是脑出血（ICH）后良好预后的障碍。作为炎症和脂质代谢的调节剂，肝脏 X 受体 (LXR) 有可能改变小胶质细胞/巨噬细胞 (M/M) 表型，并通过促进胆固醇流出和吞噬细胞再循环来协助组织修复。为了支持潜在的临床转化，在实验性 ICH 中检查了增强 LXR 信号传导的好处。方法 用 LXR 激动剂 GW3965 或载体治疗胶原酶诱导的 ICH 小鼠。在多个时间点进行行为测试。使用具有 T2 加权、扩散张量成像和动态对比增强 MRI 序列的多模态 MRI 评估病变和血肿体积以及其他脑参数。对固定的脑冷冻切片进行染色，并应用共聚焦显微镜检测 LXR 下游基因、M/M 表型、脂质/胆固醇负载的吞噬细胞、少突胶质细胞谱系细胞和神经干细胞。还使用了蛋白质印迹和实时 qPCR。CX3CR1CreER：Rosa26iDTR 小鼠用于 M/M 耗尽实验。结果GW3965治疗减少了病灶体积和白质损伤，并促进血肿清除。治疗小鼠上调 LXR 下游基因，包括 ABCA1 和载脂蛋白 E，并且 M/M 密度降低，明显从促炎性白细胞介素 1β+ 调节表型转变为精氨酸酶 1+CD206+ 调节表型。在 GW3965 小鼠中观察到较少的胆固醇晶体或充满髓磷脂碎片的吞噬细胞。LXR 激活增加了血肿周围区域中 Olig2+PDGFRα+ 前体细胞和 Olig2+CC1+ 成熟少突胶质细胞的数量，并增加了病灶和室下区中 SOX2+ 或巢蛋白 + 神经干细胞的数量。MRI 结果支持 GW3965 可以更好地恢复病变，并且功能性转棒活动恢复到 ICH 前值证实了这一点。在 CX3CR1CreER: Rosa26iDTR 小鼠中，GW3965 的治疗效果因 M/M 耗尽而被消除。结论 使用 GW3965 进行 LXR 激动可减少脑损伤，促进 M/M 的有益特性，并促进组织修复，从而增强胆固醇循环。可根据合理要求提供数据。支持本研究结果的数据可根据合理要求从相应作者处获得。