Department of Neurology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210002, Jiangsu, China.
Division of Life Sciences and Medicine, Department of Neurology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, 230001, Anhui, China.
J Neuroinflammation. 2023 Jun 23;20(1):148. doi: 10.1186/s12974-023-02819-5.
Neuroinflammation is a vital pathophysiological process during ischemic stroke. Activated astrocytes play a major role in inflammation. Lipocalin-2 (LCN2), secreted by activated astrocytes, promotes neuroinflammation. Pyroptosis is a pro-inflammatory form of programmed cell death that has emerged as a new area of research in stroke. Nevertheless, the potential role of LCN2 in astrocyte pyroptosis remains unclear.
An ischemic stroke model was established by middle cerebral artery occlusion (MCAO) in vivo. In this study, in vitro, oxygen-glucose deprivation and reoxygenation (O/R) were applied to cultured astrocytes. 24p3R (the LCN2 receptor) was inhibited by astrocyte-specific adeno-associated virus (AAV-GFAP-24p3Ri). MCC950 and Nigericin sodium salt (Nig) were used to inhibit or promote the activation of NLRP3 inflammasome pharmacologically, respectively. Histological and biochemical analyses were performed to assess astrocyte and neuron death. Additionally, the neurological deficits of mice were evaluated.
LCN2 expression was significantly induced in astrocytes 24 h after stroke onset in the mouse MCAO model. Lcn2 knockout (Lcn2) mice exhibited reduced infarct volume and improved neurological and cognitive functions after MCAO. LCN2 and its receptor 24p3R were colocalized in astrocytes. Mechanistically, suppression of 24p3R by AAV-GFAP-24p3Ri alleviated pyroptosis-related pore formation and the secretion of pro-inflammatory cytokines via LCN2, which was then reversed by Nig-induced NLRP3 inflammasome activation. Astrocyte pyroptosis was exacerbated in Lcn2 mice by intracerebroventricular administration of recombinant LCN2 (rLCN2), while this aggravation was restricted by blocking 24p3R or inhibiting NLRP3 inflammasome activation with MCC950.
LCN2/24p3R mediates astrocyte pyroptosis via NLRP3 inflammasome activation following cerebral ischemia/reperfusion injury.
神经炎症是缺血性中风过程中的一个重要病理生理过程。激活的星形胶质细胞在炎症中起主要作用。脂钙蛋白-2（LCN2）由激活的星形胶质细胞分泌，促进神经炎症。细胞焦亡是一种新出现的细胞程序性死亡形式，已成为中风研究的一个新领域。然而，LCN2 在星形胶质细胞细胞焦亡中的潜在作用尚不清楚。
通过体内大脑中动脉闭塞（MCAO）建立缺血性中风模型。在本研究中，体外应用氧葡萄糖剥夺和再氧合（O/R）培养星形胶质细胞。星形胶质细胞特异性腺相关病毒（AAV-GFAP-24p3Ri）抑制 24p3R（LCN2 受体）。MCC950 和 Nigericin 钠盐（Nig）分别用于抑制或促进 NLRP3 炎性体的激活。进行组织学和生化分析以评估星形胶质细胞和神经元死亡。此外，评估了小鼠的神经功能缺损。
在 MCAO 模型中，小鼠中风后 24 小时星形胶质细胞中 LCN2 的表达明显增加。Lcn2 敲除（Lcn2）小鼠在 MCAO 后梗死体积减小，神经功能和认知功能改善。LCN2 和其受体 24p3R 在星形胶质细胞中存在共定位。机制上，AAV-GFAP-24p3Ri 抑制 24p3R 通过 LCN2 减轻与细胞焦亡相关的孔形成和促炎细胞因子的分泌，然后被 Nig 诱导的 NLRP3 炎性体激活所逆转。Lcn2 小鼠脑室内给予重组 LCN2（rLCN2）可加剧星形胶质细胞细胞焦亡，而用 MCC950 阻断 24p3R 或抑制 NLRP3 炎性体激活可限制这种加重。
LCN2/24p3R 通过 NLRP3 炎性体激活介导脑缺血再灌注损伤后的星形胶质细胞细胞焦亡。
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