Positive feedback loop via astrocytes causes chronic inflammation in virus-associated myelopathy
Positive feedback loop via astrocytes causes chronic inflammation in virus-associated myelopathy
复制标题
DOI：
10.1093/brain/awt183
复制
发表时间：
2013-09-01
期刊：
影响因子：
14.5
通讯作者：
Yamano, Yoshihisa
中科院分区：
文献类型：
--
作者：
Ando, Hitoshi;Sato, Tomoo;Yamano, Yoshihisa
人类嗜T淋巴细胞病毒1型相关性脊髓病/热带痉挛性轻瘫（HAM/TSP）是一种罕见的神经退行性疾病，其特征是脊髓慢性炎症。我们推测趋化因子驱动的正反馈回路可能是HAM/TSP慢性炎症的原因。我们的目的是确定这些趋化因子的身份，它们在哪里产生，以及它们如何驱动HAM/TSP中的慢性炎症。我们发现HAM/TSP患者的脑脊液中有非常高水平的趋化因子CXCL 10（也称为IP-10）和大量表达CXCL 10结合受体CXCR 3的细胞。组织学分析显示，星形胶质细胞是HAM/TSP患者脊髓中CXCL 10的主要生产者。将人星形细胞瘤细胞与HAM/TSP患者的CD 4（+）T细胞共培养显示，星形细胞响应于CD 4（+）T细胞分泌的IFN-γ产生CXCL 10。趋化性试验结果表明，CXCL 10诱导外周血单核细胞迁移到中枢神经系统，抗CXCL 10中和抗体可以破坏这种迁移。简而言之，我们推断中枢神经系统中人类T淋巴细胞病毒1型感染的细胞产生IFN-γ，诱导星形胶质细胞分泌CXCL 10，CXCL 10通过CXCR 3招募更多的感染细胞到该区域，构成了导致慢性炎症的T辅助细胞1型中心正反馈回路。
Human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare neurodegenerative disease characterized by chronic inflammation in the spinal cord. We hypothesized that a positive feedback loop driven by chemokines may be responsible for the chronic inflammation in HAM/TSP. We aimed to determine the identity of these chemokines, where they are produced, and how they drive chronic inflammation in HAM/TSP. We found that patients with HAM/TSP have extraordinarily high levels of the chemokine CXCL10 (also known as IP-10) and an abundance of cells expressing the CXCL10-binding receptor CXCR3 in the cerebrospinal fluid. Histological analysis revealed that astrocytes are the main producers of CXCL10 in the spinal cords of patients with HAM/TSP. Co-culture of human astrocytoma cells with CD4(+) T cells from patients with HAM/TSP revealed that astrocytes produce CXCL10 in response to IFN-gamma secreted by CD4(+) T cells. Chemotaxis assays results suggest that CXCL10 induces migration of peripheral blood mononuclear cells to the central nervous system and that anti-CXCL10 neutralizing antibody can disrupt this migration. In short, we inferred that human T-lymphotropic virus type 1-infected cells in the central nervous system produce IFN-gamma that induces astrocytes to secrete CXCL10, which recruits more infected cells to the area via CXCR3, constituting a T helper type 1-centric positive feedback loop that results in chronic inflammation.