Lipocalin-2 Protein Deficiency Ameliorates Experimental Autoimmune Encephalomyelitis THE PATHOGENIC ROLE OF LIPOCALIN-2 IN THE CENTRAL NERVOUS SYSTEM AND PERIPHERAL LYMPHOID TISSUES
Lipocalin-2 Protein Deficiency Ameliorates Experimental Autoimmune Encephalomyelitis THE PATHOGENIC ROLE OF LIPOCALIN-2 IN THE CENTRAL NERVOUS SYSTEM AND PERIPHERAL LYMPHOID TISSUES
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DOI：
10.1074/jbc.m113.542282
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发表时间：
2014-06-13
影响因子：
4.8
通讯作者：
Suk, Kyoungho
中科院分区：
文献类型：
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作者：
Nam, Youngpyo;Kim, Jong-Heon;Suk, Kyoungho
脂质运载蛋白-2（LCN 2）在细胞生长、迁移/侵袭、分化和死亡/存活等多种细胞过程中发挥重要作用。此外，最近的研究表明，神经胶质细胞的LCN 2表达和分泌是由中枢神经系统中的炎症刺激诱导的。本研究旨在研究LCN 2在实验性自身免疫性脑脊髓炎（EAE）中的表达调控，并确定LCN 2在疾病过程中的作用。发现LCN 2表达在EAE诱导后的脊髓和次级淋巴组织中强烈增加。在脊髓中，星形胶质细胞和小胶质细胞分别是表达LCN 2及其受体24 p3 R的主要细胞类型，而在脾脏中，LCN 2和24 p3 R分别在中性粒细胞和树突状细胞中高度表达。此外，与野生型动物相比，Lcn 2缺陷小鼠的疾病严重程度、炎性浸润、脱髓鞘、神经胶质活化、炎性介质的表达和MOG特异性T细胞的增殖显著减弱。培养的髓鞘少突胶质细胞糖蛋白特异性T细胞在用重组LCN 2蛋白处理后表现出IL 17 a、Ifng、Rorc和Tbet的表达增加。此外，LCN 2处理的神经胶质细胞表达更高水平的促炎细胞因子，趋化因子和MMP-9。连续转移和重组LCN 2蛋白注射实验表明，LCN 2在脊髓和外周免疫器官中的表达有助于EAE的发生。综上所述，这些结果表明LCN 2是EAE中自身免疫炎症和疾病发展的关键介质，并表明LCN 2被认为是多发性硬化症的潜在治疗靶点。
Lipocalin-2 (LCN2) plays an important role in cellular processes as diverse as cell growth, migration/invasion, differentiation, and death/survival. Furthermore, recent studies indicate that LCN2 expression and secretion by glial cells are induced by inflammatory stimuli in the central nervous system. The present study was undertaken to examine the regulation of LCN2 expression in experimental autoimmune encephalomyelitis (EAE) and to determine the role of LCN2 in the disease process. LCN2 expression was found to be strongly increased in spinal cord and secondary lymphoid tissues after EAE induction. In spinal cords astrocytes and microglia were the major cell types expressing LCN2 and its receptor 24p3R, respectively, whereas in spleens, LCN2 and 24p3R were highly expressed in neutrophils and dendritic cells, respectively. Furthermore, disease severity, inflammatory infiltration, demyelination, glial activation, the expression of inflammatory mediators, and the proliferation of MOG-specific T cells were significantly attenuated in Lcn2-deficient mice as compared with wild-type animals. Myelin oligodendrocyte glycoprotein-specific T cells in culture exhibited an increased expression of Il17a, Ifng, Rorc, and Tbet after treatment with recombinant LCN2 protein. Moreover, LCN2-treated glial cells expressed higher levels of proinflammatory cytokines, chemokines, and MMP-9. Adoptive transfer and recombinant LCN2 protein injection experiments suggested that LCN2 expression in spinal cord and peripheral immune organs contributes to EAE development. Taken together, these results imply LCN2 is a critical mediator of autoimmune inflammation and disease development in EAE and suggest that LCN2 be regarded a potential therapeutic target in multiple sclerosis.