Glucocorticoid resistance of allogeneic T cells alters the gene expression profile in the inflamed small intestine of mice suffering from acute graft-versus-host disease
Glucocorticoid resistance of allogeneic T cells alters the gene expression profile in the inflamed small intestine of mice suffering from acute graft-versus-host disease
复制标题
DOI：
10.1016/j.jsbmb.2019.105485
复制
发表时间：
2019-12-01
影响因子：
4.1
通讯作者：
Reichardt, Holger M.
中科院分区：
文献类型：
--
作者：
Li, Hu;Kaiser, Tina K.;Reichardt, Holger M.
糖皮质激素（GCs）在控制急性移植物抗宿主病（aGvHD）中发挥重要作用，aGvHD是同种异体造血干细胞移植的常见并发症。GCs的抗炎活性主要归因于T细胞和巨噬细胞的调节，因此遗传诱导的这两种细胞类型中的任何一种的GC抗性都会加重aGvHD。由于目前只知道少数基因在这些条件下受到差异调节，我们使用高通量定量PCR的微流控动态阵列平台分析了54个候选基因在aGvHD小鼠炎症小肠中的表达，当同种异体T细胞或宿主骨髓细胞都具有GC抗性时。细胞因子（如Il2、Il6）、趋化因子（如Ccl2、Cxcl1）、细胞表面受体（如Fas1、Cda4）和细胞内分子（如Dusp1、Arg1）等大多数基因在移植GC耐药异体T细胞的小鼠中表达上调。此外，与能量代谢相关的几个基因（如Glut1）的表达也发生了改变。令人惊讶的是，在aGvHD诱导后，尽管它们的致命病程，但含有GC抗性骨髓细胞的小鼠的基因表达几乎没有变化。为了确定炎症小肠中受同种异体T细胞GC抗性影响的其他基因，我们进行了RNAseq分析，发现了500多个差异表达转录物（例如Cxcr6， Glut3, Otc, Aoc1, Il1r1, Sphk1），这些转录物富集于与炎症和组织分解相关的生物过程中。基因表达的变化可以在疾病爆发时得到证实，但在临床前阶段几乎没有使用高通量定量PCR。对其中一些基因的进一步分析显示，这些基因在T细胞、肠上皮细胞和巨噬细胞中具有高度选择性的表达模式，这与它们在疾病进展过程中的调控相关。总之，我们确定了移植的异体T细胞GC抗性引起的基因表达谱改变，这可能有助于确定aGvHD治疗的新靶点。
Glucocorticoids (GCs) play an important role in controlling acute graft-versus-host disease (aGvHD), a frequent complication of allogeneic hematopoietic stem cell transplantation. The anti-inflammatory activity of GCs is mainly ascribed to the modulation of T cells and macrophages, for which reason a genetically induced GC resistance of either of these cell types causes aggravated aGvHD. Since only a few genes are currently known that are differentially regulated under these conditions, we analyzed the expression of 54 candidate genes in the inflamed small intestine of mice suffering from aGvHD when either allogeneic T cells or host myeloid cells were GC resistant using a microfluidic dynamic array platform for high-throughput quantitative PCR. The majority of genes categorized as cytokines (e.g. Il2, Il6), chemokines (e.g. Ccl2, Cxcl1), cell surface receptors (e.g. Fas1, Cda4) and intracellular molecules (e.g. Dusp1, Arg1) were upregulated in mice transplanted with GC resistant allogeneic T cells. Moreover, the expression of several genes linked to energy metabolism (e.g. Glut1) was altered. Surprisingly, mice harboring GC resistant myeloid cells showed almost no changes in gene expression despite their fatal disease course after aGvHD induction. To identify additional genes in the inflamed small intestine that were affected by a GC resistance of allogeneic T cells, we performed an RNAseq analysis, which uncovered more than 500 differentially expressed transcripts (e.g. Cxcr6, Glut3, Otc, Aoc1, Il1r1, Sphk1) that were enriched for biological processes associated with inflammation and tissue disassembly. The changes in gene expression could be confirmed during full-blown disease but hardly any of them in the preclinical phase using high-throughput quantitative PCR. Further analysis of some of these genes revealed a highly selective expression pattern in T cells, intestinal epithelial cells and macrophages, which correlated with their regulation during disease progression. Collectively, we identified an altered gene expression profile caused by GC resistance of transplanted allogeneic T cells, which could help to define new targets for aGvHD therapy.