Systemically Silencing Long Non-coding RNAs Maclpil With Short Interfering RNA Nanoparticles Alleviates Experimental Ischemic Stroke by Promoting Macrophage Apoptosis and Anti-inflammatory Activation.
Systemically Silencing Long Non-coding RNAs Maclpil With Short Interfering RNA Nanoparticles Alleviates Experimental Ischemic Stroke by Promoting Macrophage Apoptosis and Anti-inflammatory Activation.
复制标题
DOI：
10.3389/fcvm.2022.876087
复制
发表时间：
2022
影响因子：
3.6
通讯作者：
中科院分区：
文献类型：
--
作者：
Maclpil 是一种促炎性长非编码 RNA，在缺血性脑中单核细胞衍生的巨噬细胞上高表达。本研究调查了系统性递送纳米颗粒 Maclpil 短干扰 RNA (siRNA) 对小鼠模型实验性缺血性中风的影响和机制。通过大脑中动脉闭塞在雄性 C57BL/6 小鼠中诱导缺血性中风（局灶性脑缺血）。三小时后，给小鼠静脉内注射Maclpil siRNA或扰乱siRNA纳米颗粒。用 Maclpil 或 scramble siRNA 转染骨髓细胞来源的巨噬细胞，并进行氧糖剥夺培养。通过组织学、流式细胞术、蛋白质印迹和定量 PCR 分析评估沉默 Maclpil 对中风结果、神经炎症和巨噬细胞命运的影响。中风诱导后三天，siRNA 沉默 Maclpil 显着减少了缺血性梗塞面积并改善了神经行为。沉默 Maclpil 还显着减弱了缺血半球中单核细胞衍生的巨噬细胞、CD4+ T 细胞和 CD8+ T 细胞的积累，而不影响小胶质细胞的细胞结构。相反，Maclpil siRNA 治疗后，小鼠外周血中的骨髓细胞和两种 T 细胞亚群均升高。在模拟体外缺氧和低血糖的氧糖剥夺条件下，Maclpil siRNA 沉默增强了巨噬细胞凋亡，同时上调了促凋亡的 Bax 和 caspase 3 表达。敲除 Maclpil 的 siRNA 使巨噬细胞从经典的促炎性激活转向抗炎性替代激活，精氨酸酶 1、Ym1 和 Fizz1 增加以及诱导型一氧化氮合酶、IL-1β 和 TNF-α mRNA 水平降低就证明了这一点。与巨噬细胞表型转换一致，通过 siRNA 沉默 Maclpil 可增强脂肪酸氧化，如 3 种关键代谢酶（ACADM、ACADVL 和 HADHA）的 mRNA 水平增加所示。通过 siRNA 纳米粒子系统性沉默 Maclpil，可通过促进巨噬细胞凋亡和抗炎替代激活来减轻实验性缺血性中风。识别和靶向 Maclpil 人类同源物可能有助于开发中风临床管理的新疗法。
Maclpil is a proinflammatory long non-coding RNA highly expressed on monocyte-derived macrophages in the ischemic brain. This study investigated the impact and the mechanisms of systemically delivering nanoparticle Maclpil short interfering RNA (siRNA) on experimental ischemic stroke in a mouse model. Ischemic stroke (focal cerebral ischemia) was induced in male C57BL/6 mice through the middle cerebral artery occlusion. Three hours thereafter, mice were intravenously injected with Maclpil siRNA or scramble siRNA nanoparticles. Bone marrow cell-derived macrophages were transfected with Maclpil or scramble siRNA and subjected to oxygen glucose deprivation culture. The influence of silencing Maclpil on stroke outcomes, neuroinflammation, and macrophage fates was assessed via histology, flow cytometry, Western blotting, and quantitative PCR analysis. Three days following stroke induction, siRNA silencing Maclpil substantially reduced ischemic infarction size and improved neurological behaviors. Silencing Maclpil also markedly attenuated the accumulation of monocyte-derived macrophages, CD4+ T cells, and CD8+ T cells in the ischemic hemisphere without affecting microglia cellularity. Reciprocally, myeloid cells and both subsets of T cells were elevated in mouse peripheral blood following Maclpil siRNA treatment. Under oxygen glucose deprivation conditions that mimicked hypoxia and hypoglycemia in vitro, Maclpil siRNA silencing augmented macrophage apoptosis in conjunction with upregulation of proapoptotic Bax and caspase 3 expressions. siRNA knocking down Maclpil skewed macrophages from proinflammatory classical toward anti-inflammatory alternative activation as evidenced by increased arginase 1, Ym1, and Fizz1 and reduced inducible nitric oxide synthase, IL-1β, and TNF-α mRNA levels. Consistent with macrophage phenotype switching, silencing Maclpil by siRNA enhanced fatty acid oxidation as indicated by increased mRNA levels of 3 key metabolic enzymes (ACADM, ACADVL, and HADHA). Systemically silencing Maclpil by siRNA nanoparticles attenuated experimental ischemic stroke by promoting macrophage apoptosis and anti-inflammatory alternative activation. Identifying and targeting Maclpil human homolog(s) may help develop a novel therapy for stroke clinical management.
登录
查看更多内容
影响因子：
--
作者：
Morley SC
通讯作者：
Morley SC
影响因子：
4.3
作者：
Remmerie A;Scott CL
通讯作者：
Scott CL
影响因子：
8.3
作者：
Dykstra-Aiello C;Jickling GC;Ander BP;Shroff N;Zhan X;Liu D;Hull H;Orantia M;Stamova BS;Sharp FR
通讯作者：
Sharp FR
褪黑激素通过 STAT3 通路调节小胶质细胞/巨噬细胞极化至抗炎表型，从而预防缺血性中风
影响因子：
5.5
作者：
Liu, Zong-Jian;Ran, Yuan-Yuan;Xi, Jia-Ning
通讯作者：
Xi, Jia-Ning
中风引起的全身脑部炎症
影响因子：
48
作者：
Shi, Kaibin;Tian, De-Cai;Shi, Fu-Doug
通讯作者：
Shi, Fu-Doug