Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China.
Department of Neurosurgery, Stanford University School of Medicine, 1201 Welch Road, MSLS Building, Stanford, USA.
Theranostics. 2024 Jan 1;14(1):159-175. doi: 10.7150/thno.88678. eCollection 2024.
Ischemic stroke poses a significant health burden with limited treatment options. Lymphocyte Cytosolic Protein 1 (LCP1) facilitates cell migration and immune responses by aiding in actin polymerization, cytoskeletal rearrangements, and phagocytosis. We have demonstrated that the long non-coding RNA (lncRNA) Maclpil silencing in monocyte-derived macrophages (MoDMs) led to LCP1 inhibition, reducing ischemic brain damage. However, the role of LCP1 of MoDMs in ischemic stroke remains unknown. We investigated the impact of LCP1 on ischemic brain injury and immune cell signaling and metabolism. We found that knockdown of LCP1 in MoDMs demonstrated robust protection against ischemic infarction and improved neurological behaviors in mice. Utilizing the high-dimensional CyTOF technique, we demonstrated that knocking down LCP1 in MoDMs led to a reduction in neuroinflammation and attenuation of lymphopenia, which is linked to immunodepression. It also showed altered immune cell signaling by modulating the phosphorylation levels of key kinases and transcription factors, including p-PLCg2, p-ERK1/2, p-EGFR, p-AKT, and p4E-BP1 as well as transcription factors like p-STAT1, p-STAT3, and p-STAT4. Further bioinformatic analysis indicated that Akt and EGFR are particularly involved in fatty acid metabolism and glycolysis. Indeed, single-cell sequencing analysis confirmed that enrichment of fatty acid and glycolysis metabolism in Lcp1 monocytes/macrophages. Furthermore, Lcp1 cells exhibited enhanced oxidative phosphorylation, chemotaxis, migration, and ATP biosynthesis pathways. experiments confirmed the role of LCP1 in regulating mitochondrial function and fatty acid uptake. These findings contribute to a deeper understanding of LCP1 in the context of ischemic stroke and provide valuable insights into potential therapeutic strategies targeting LCP1 and metabolic pathways, aiming to attenuating neuroinflammation and lymphopenia.
缺血性中风是一种具有重大健康负担的疾病，目前治疗选择有限。淋巴细胞胞浆蛋白 1（LCP1）通过帮助肌动蛋白聚合、细胞骨架重排和吞噬作用，促进细胞迁移和免疫反应。我们已经证明，单核细胞衍生的巨噬细胞（MoDMs）中的长非编码 RNA（lncRNA）Maclpil 沉默导致 LCP1 抑制，从而减少缺血性脑损伤。然而，MoDMs 中的 LCP1 在缺血性中风中的作用尚不清楚。我们研究了 LCP1 对缺血性脑损伤和免疫细胞信号转导和代谢的影响。我们发现，MoDMs 中的 LCP1 敲低可显著保护缺血性梗死并改善小鼠的神经行为。利用高维 CyTOF 技术，我们证明 MoDMs 中的 LCP1 敲低可导致神经炎症减少和淋巴细胞减少减轻，这与免疫抑制有关。它还通过调节关键激酶和转录因子的磷酸化水平，包括 p-PLCg2、p-ERK1/2、p-EGFR、p-AKT 和 p4E-BP1 以及转录因子如 p-STAT1、p-STAT3 和 p-STAT4，改变免疫细胞信号转导。进一步的生物信息学分析表明，Akt 和 EGFR 特别参与脂肪酸代谢和糖酵解。事实上，单细胞测序分析证实了 Lcp1 单核细胞/巨噬细胞中脂肪酸和糖酵解代谢的富集。此外，Lcp1 细胞表现出增强的氧化磷酸化、趋化性、迁移和 ATP 生物合成途径。实验证实了 LCP1 在调节线粒体功能和脂肪酸摄取中的作用。这些发现有助于更深入地了解 LCP1 在缺血性中风中的作用，并为针对 LCP1 和代谢途径的潜在治疗策略提供有价值的见解，旨在减轻神经炎症和淋巴细胞减少。
