Activation of Nrf2 to Optimise Immune Responses to Intracerebral Haemorrhage.
Activation of Nrf2 to Optimise Immune Responses to Intracerebral Haemorrhage.
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DOI：
10.3390/biom12101438
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发表时间：
2022-10-07
期刊：
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
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脑实质出血可能是毁灭性的。这表现为头部创伤后自发性脑出血（ICH），并在血管性痴呆的背景下。随机对照试验尚未可靠地证明旨在限制ICH血肿扩大的止血治疗和减少血肿体积的手术方法是有效的。因此，调节可能引起继发性脑损伤的ICH的病理生理反应的治疗是有吸引力的。ICH后，小胶质细胞和单核细胞衍生的细胞被募集到血肿周围环境，在那里它们吞噬血肿分解产物并分泌炎性细胞因子，这可能引发保护性和有害反应。转录因子Nrf2由氧化应激激活，在中枢神经系统小胶质细胞和大胶质细胞中高度表达。当激活时，Nrf2诱导转录程序，其特征在于增加抗氧化剂、血红素和重金属解毒和蛋白酶抑制基因的表达，以及抑制促炎因子。因此，Nrf2激活可能通过增强对氧化应激和重金属毒性的抵抗力来促进对ICH的适应性保护免疫细胞反应，同时限制有害的炎症信号传导，这可能导致进一步的血脑屏障功能障碍和脑水肿。在这篇综述中，我们考虑了免疫细胞对ICH的反应，以及这些反应可能是如何通过Nrf2激活来调节的。最后，我们提出了利用Nrf2改善ICH患者预后的潜在治疗策略。
Haemorrhage into the brain parenchyma can be devastating. This manifests as spontaneous intracerebral haemorrhage (ICH) after head trauma, and in the context of vascular dementia. Randomised controlled trials have not reliably shown that haemostatic treatments aimed at limiting ICH haematoma expansion and surgical approaches to reducing haematoma volume are effective. Consequently, treatments to modulate the pathophysiological responses to ICH, which may cause secondary brain injury, are appealing. Following ICH, microglia and monocyte derived cells are recruited to the peri-haematomal environment where they phagocytose haematoma breakdown products and secrete inflammatory cytokines, which may trigger both protective and harmful responses. The transcription factor Nrf2, is activated by oxidative stress, is highly expressed by central nervous system microglia and macroglia. When active, Nrf2 induces a transcriptional programme characterised by increased expression of antioxidant, haem and heavy metal detoxification and proteostasis genes, as well as suppression of proinflammatory factors. Therefore, Nrf2 activation may facilitate adaptive-protective immune cell responses to ICH by boosting resistance to oxidative stress and heavy metal toxicity, whilst limiting harmful inflammatory signalling, which can contribute to further blood brain barrier dysfunction and cerebral oedema. In this review, we consider the responses of immune cells to ICH and how these might be modulated by Nrf2 activation. Finally, we propose potential therapeutic strategies to harness Nrf2 to improve the outcomes of patients with ICH.
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