During multiple sclerosis (MS), an inflammatory and neurodegenerative disease of the central nervous system (CNS), symptoms, and outcomes are determined by the location of inflammatory lesions. While we and others have shown that T cell cytokines differentially regulate leukocyte entry into perivascular spaces and regional parenchymal localization in murine models of MS, the molecular mechanisms of this latter process are poorly understood. Here, we demonstrate that astrocytes exhibit region-specific responses to T cell cytokines that promote hindbrain versus spinal cord neuroinflammation. Analysis of cytokine receptor expression in human astrocytes showed region-specific responsiveness to Th1 and Th17 inflammatory cytokines. Consistent with this, human and murine astrocytes treated with these cytokines exhibit differential expression of the T cell localizing molecules VCAM-1 and CXCR7 that is both cytokine and CNS region-specific. Using in vivo models of spinal cord versus brain stem trafficking of myelin-specific T cells and astrocyte-specific deletion strategies, we confirmed that Th1 and Th17 cytokines differentially regulate astrocyte expression of VCAM-1 and CXCR7 in these locations. Finally, stereotaxic injection of individual cytokines into the hindbrain or spinal cord revealed region- and cytokine-specific modulation of localizing cue expression by astrocytes. These findings identify a role for inflammatory cytokines in mediating local astrocyte-dependent mechanisms of immune cell trafficking within the CNS during neuroinflammation.

中文翻译：

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星形胶质细胞-T 细胞串扰调节区域特异性神经炎症。

在多发性硬化症 (MS) 期间，中枢神经系统 (CNS) 的炎症和神经退行性疾病、症状和结果由炎症病变的位置决定。虽然我们和其他人已经证明 T 细胞细胞因子在 MS 小鼠模型中差异调节白细胞进入血管周围空间和区域实质定位，但对后一种过程的分子机制知之甚少。在这里，我们证明星形胶质细胞对促进后脑与脊髓神经炎症的 T 细胞因子表现出区域特异性反应。对人星形胶质细胞中细胞因子受体表达的分析显示对 Th1 和 Th17 炎性细胞因子的区域特异性反应。与此相符，用这些细胞因子处理的人和鼠星形胶质细胞表现出 T 细胞定位分子 VCAM-1 和 CXCR7 的差异表达，它们都是细胞因子和 CNS 区域特异性的。使用髓磷脂特异性 T 细胞和星形胶质细胞特异性缺失策略的脊髓与脑干运输的体内模型，我们证实 Th1 和 Th17 细胞因子在这些位置差异调节 VCAM-1 和 CXCR7 的星形胶质细胞表达。最后，将单个细胞因子立体定向注射到后脑或脊髓中，揭示了星形胶质细胞对定位线索表达的区域和细胞因子特异性调节。这些发现确定了炎症细胞因子在神经炎症期间介导 CNS 内免疫细胞运输的局部星形胶质细胞依赖性机制中的作用。