LINGO-1 deficiency promotes nerve regeneration through reduction of cell apoptosis, inflammation, and glial scar after spinal cord injury in mice
LINGO-1 deficiency promotes nerve regeneration through reduction of cell apoptosis, inflammation, and glial scar after spinal cord injury in mice
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DOI：
10.1016/j.expneurol.2019.112965
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发表时间：
2019-10-01
影响因子：
5.3
通讯作者：
Zeng, Yuan-Shan
中科院分区：
文献类型：
--
作者：
Huang, Li-Jun;Li, Ge;Zeng, Yuan-Shan
富含亮氨酸重复序列和免疫球蛋白结构域的蛋白1(LINGO-1)是一种跨膜蛋白，负向调节中枢神经系统的神经再生。Lingo-1在中枢神经损伤后表达上调，并伴随细胞死亡。损伤微环境中的Lingo-1和细胞死亡都被认为限制了神经再生，但Lingo-1和细胞死亡之间的关系尚未确定。为了研究LINGO-1基因缺失是否能改善脊髓损伤(SCI)后的脊髓微环境并有助于细胞存活，我们建立了LINGO-1基因敲除(KO)小鼠。对这些小鼠和野生型对照小鼠进行脊髓横断实验。脊髓横断后14天，免疫组织化学染色观察细胞凋亡、炎症反应、胶质瘢痕形成和神经纤维生长情况。结果表明，LINGO-1KO小鼠caspase-3、转移酶介导的脱氧尿嘧啶核苷缺口末端标记(TUNEL)、离子钙结合接头分子1(IBA1)、胶质纤维酸性蛋白(GFAP)和硫酸软骨素蛋白多糖(CSPGs)的表达较对照组显著降低。与野生型相比，Lingo-1KO小鼠脊髓损伤部位神经丝的表达显著增加。这些结果表明，LINGO-1在细胞死亡、炎症反应和胶质瘢痕形成等损伤微环境中起着关键作用。重要的是，Lingo-1的缺失和积极的微环境可能会在促进神经纤维再生方面发挥协同作用。因此，抑制LINGO-1可能是促进脊髓损伤后神经再生的治疗策略。
Leucine-rich repeat and immunoglobulin domain-containing protein 1 (LINGO-1) is a transmembrane protein that negatively regulates neural regeneration in the central nervous system. LINGO-1 expression is up-regulated after central nerve injury, and is accompanied by cell death. Both LINGO-1 and cell death in the injury microenvironment are thought to limit neural regeneration, but the relationship between LINGO-1 and cell death has not been characterized. To investigate whether LINGO-1 deletion improves the spinal cord microenvironment after spinal cord injury (SCI) and contributes to cell survival, we generated LINGO-1 knockout (KO) mice. These mice and wild-type control mice were subjected to spinal cord transection. Fourteen days after spinal cord transection, cell apoptosis, inflammation, glial scar, and growth of nerve fibers were evaluated by immunostaining. The results showed that LINGO-1 KO mice demonstrated a profound reduction in expression of caspase-3, transferase-mediated deoxyuridine triphosphate biotin nick end labeling (TUNEL), ionized calcium binding adapter molecule 1 (IBA1), glial fibrillary acidic protein (GFAP), and chondroitin sulfate proteoglycans (CSPGs) compared to controls. In contrast, expression of neurofilament (NF) at the SCI site in LINGO-1 KO mice was markedly increased compared to that in wild-type mice. These results suggested that LINGO-1 plays a critical role in the injury microenvironment in processes such as cell death, inflammatory response, and glial scar formation. Importantly, LINGO-1 deletion and a positive microenvironment may exert synergistic effects to promote nerve fiber regeneration. Therefore, inhibition of LINGO-1 may be a therapeutic strategy to promote neural regeneration following SCI.