Host interleukin 6 production regulates inflammation but not tryptophan metabolism in the brain during murine GVHD
Host interleukin 6 production regulates inflammation but not tryptophan metabolism in the brain during murine GVHD
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DOI：
10.1172/jci.insight.93726
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发表时间：
2017-07-20
期刊：
影响因子：
8
通讯作者：
Drobyski, William R.
中科院分区：
文献类型：
--
作者：
Belle, Ludovic;Zhou, Vivian;Drobyski, William R.
移植物抗宿主病（GVHD）诱导外周靶器官的病理损伤，导致充分表征的器官特异性临床表现。然而，GVHD患者也可以有影响整体认知功能的行为改变，但GVHD改变大脑中炎症和生化途径的程度仍然知之甚少。在目前的研究中，我们采用互补的小鼠GVHD模型来证明同种异体反应性供体T细胞在大脑中积累，并影响与特定行为异常相关的促炎细胞因子环境。宿主IL-6被鉴定为关键的细胞因子介体，宿主吲哚胺2，3-双加氧酶（IDO-1）也是如此，其在GVHD中以IL-6依赖性方式在小胶质细胞中上调，并伴随中缝背核和前额皮质中色氨酸代谢失调。IL-6信号通路的阻断显著降低了供体T细胞积累、炎性细胞因子基因表达和宿主小胶质细胞扩增，但不能逆转GVHD诱导的色氨酸代谢物失调。因此，这些结果表明，IL-6信号传导的抑制减弱了神经炎症，但并没有逆转GVHD期间大脑中的所有代谢异常，这也可能对用IL-6定向方法治疗其他基于T细胞的免疫疗法后发生的神经毒性具有意义。
Graft-versus-host disease (GVHD) induces pathological damage in peripheral target organs leading to well-characterized, organ-specific clinical manifestations. Patients with GVHD, however, can also have behavioral alterations that affect overall cognitive function, but the extent to which GVHD alters inflammatory and biochemical pathways in the brain remain poorly understood. In the current study, we employed complementary murine GVHD models to demonstrate that alloreactive donor T cells accumulate in the brain and affect a proinflammatory cytokine milieu that is associated with specific behavioral abnormalities. Host IL-6 was identified as a pivotal cytokine mediator, as was host indoleamine 2,3-dioxygenase (IDO-1), which was upregulated in GVHD in an IL-6-dependent manner in microglial cells and was accompanied by dysregulated tryptophan metabolism in the dorsal raphe nucleus and prefrontal cortex. Blockade of the IL-6 signaling pathway significantly reduced donor T cell accumulation, inflammatory cytokine gene expression, and host microglial cell expansion, but did not reverse GVHD-induced tryptophan metabolite dysregulation. Thus, these results indicate that inhibition of IL-6 signaling attenuates neuroinflammation, but does not reverse all of the metabolic abnormalities in the brain during GVHD, which may also have implications for the treatment of neurotoxicity occurring after other T cell-based immune therapies with IL-6-directed approaches.